Dissertations / Theses on the topic 'BMP'
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1
Wardle, Fiona Claire. "Regulation of the BMP signalling pathway by BMP-1 related metalloproteases." Thesis, University College London (University of London), 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.287477.
2
Aramaki, Toshihiro. "Jiraiya Attenuates BMP Signaling by Interfering with Type-II BMP Receptors in Neuroectodermal Patterning." Kyoto University, 2011. http://hdl.handle.net/2433/142060.
3
Zanchettin, Gianpietro. "BMP axis in cancer cachexia." Doctoral thesis, Università degli studi di Padova, 2017. http://hdl.handle.net/11577/3425867.
Abstract:
BACKGROUND
Cancer cachexia is a devastating metabolic syndrome characterized by systemic inflammation and massive muscle and adipose tissue wasting. Although cancer cachexia is responsible for about 25% of cancer deaths, no effective therapies are available, and the underlying mechanisms have not been fully elucidated.
Its occurrence complicates patients’ management, reduces tolerance to treatments and negatively affects patient quality of life. Muscle wasting, mainly due to increased protein breakdown rates, is one of the most prominent features of cachexia. Blocking muscle loss in cachexia mouse models dramatically prolongs survival even of animals in which tumor growth is not inhibited.
Recent observations showed that bone morphogenetic protein (BMP) signaling, acting through Smad1, Smad5 and Smad8 (Smad1/5/8), is a master regulator of muscle homeostasis. BMP-Smad1/5/8 axis negatively regulates a novel ubiquitin ligase (MUSA1) required for muscle loss induced by denervation.
MATERIALS AND METHODS
First aim of the present work was to test if alterations of the BMP signaling pathway occur in cancer-induced muscle wasting in patients. For this purpose we checked the state of activation of the BMP pathway in muscle of cachectic vs non–cachectic patients affected by colon, pancreatic and esophagus cancer and in control subjects. We checked by Western Blot the phosphorylation levels of Smad1/5/8 and of Smad3 and by quantitative Real-Time PCR (qRT-PCR) the expression levels of different atrophy-related genes The second aim was to evaluate the degree of muscle atrophy and distribution of muscle fibers in patients and control subjects using morphometric and immunohistochemical analyses. We also performed analysis on distribution of NCAM positive muscle fibers to assess the effect of denervation on muscle tropism.
RESULTS
From December 2014 we collected 95 rectus abdominis muscle biopsies of cancer patients and 11 from control subjects. In line with the results we obtained in C26 mice model (a well-established cancer cachexia experimental model) Smad1/5/8 phosphorylation, readout of the state of activation of the BMP pathway, was nearly completely abrogated in the muscles of cancer cachectic patients compared to cancer non-cachectic ones. Interestingly, the level of phosphorylation of Smad3 was not significantly affected suggesting specific effects of cancer growth on BMP pathway. The expression levels of different atrophy-related genes including MUSA1 were induced in the cachectic muscles. Interestingly, several BMP related genes are also changing the expression during cancer growth. We also found a correlation between suppression of BMP pathway, expression of atrophy related genes and Noggin, known to block BMP pathway.
Morphometric analysis shown that patients with cancer cachexia have smaller myofiber diameter (in particular fast type fibers) in comparison to age-matched controls. In skeletal muscle from cancer patients (either cachectic or non-cachectic) we detected a prevalence of flat shaped, angulated and severely atrophic myofibers (i.e. morphological features of denervated myofibers), big fiber-type grouping (i.e. typical hallmark of denervation/reinnervation events) and numerous NCAM positive myofibers (i.e. specific marker of denervation).
CONCLUSIONS
These findings are consistent with the hypothesis that BMP inhibition is permissive to cachexia onset. Since the reactivation of the BMP-dependent signaling and MUSA1 suppression was sufficient to prevent tumor-induced muscle atrophy in our C26 mouse model (data not shown), the present data suggest that the BMP axis can be an effective target for therapeutic approaches to counteract cachexia also in cancer patients.
The results of morphometric and immunohistochemical studies collected till now may suggest that denervation contributes to myofiber atrophy in cancer cachexia.BACKGROUND Cancer cachexia is a devastating metabolic syndrome characterized by systemic inflammation and massive muscle and adipose tissue wasting. Although cancer cachexia is responsible for about 25% of cancer deaths, no effective therapies are available, and the underlying mechanisms have not been fully elucidated. Its occurrence complicates patients’ management, reduces tolerance to treatments and negatively affects patient quality of life. Muscle wasting, mainly due to increased protein breakdown rates, is one of the most prominent features of cachexia. Blocking muscle loss in cachexia mouse models dramatically prolongs survival even of animals in which tumor growth is not inhibited. Recent observations showed that bone morphogenetic protein (BMP) signaling, acting through Smad1, Smad5 and Smad8 (Smad1/5/8), is a master regulator of muscle homeostasis. BMP-Smad1/5/8 axis negatively regulates a novel ubiquitin ligase (MUSA1) required for muscle loss induced by denervation. MATERIALS AND METHODS First aim of the present work was to test if alterations of the BMP signaling pathway occur in cancer-induced muscle wasting in patients. For this purpose we checked the state of activation of the BMP pathway in muscle of cachectic vs non–cachectic patients affected by colon, pancreatic and esophagus cancer and in control subjects. We checked by Western Blot the phosphorylation levels of Smad1/5/8 and of Smad3 and by quantitative Real-Time PCR (qRT-PCR) the expression levels of different atrophy-related genes The second aim was to evaluate the degree of muscle atrophy and distribution of muscle fibers in patients and control subjects using morphometric and immunohistochemical analyses. We also performed analysis on distribution of NCAM positive muscle fibers to assess the effect of denervation on muscle tropism. RESULTS From December 2014 we collected 95 rectus abdominis muscle biopsies of cancer patients and 11 from control subjects. In line with the results we obtained in C26 mice model (a well-established cancer cachexia experimental model) Smad1/5/8 phosphorylation, readout of the state of activation of the BMP pathway, was nearly completely abrogated in the muscles of cancer cachectic patients compared to cancer non-cachectic ones. Interestingly, the level of phosphorylation of Smad3 was not significantly affected suggesting specific effects of cancer growth on BMP pathway. The expression levels of different atrophy-related genes including MUSA1 were induced in the cachectic muscles. Interestingly, several BMP related genes are also changing the expression during cancer growth. We also found a correlation between suppression of BMP pathway, expression of atrophy related genes and Noggin, known to block BMP pathway. Morphometric analysis shown that patients with cancer cachexia have smaller myofiber diameter (in particular fast type fibers) in comparison to age-matched controls. In skeletal muscle from cancer patients (either cachectic or non-cachectic) we detected a prevalence of flat shaped, angulated and severely atrophic myofibers (i.e. morphological features of denervated myofibers), big fiber-type grouping (i.e. typical hallmark of denervation/reinnervation events) and numerous NCAM positive myofibers (i.e. specific marker of denervation). CONCLUSIONS These findings are consistent with the hypothesis that BMP inhibition is permissive to cachexia onset. Since the reactivation of the BMP-dependent signaling and MUSA1 suppression was sufficient to prevent tumor-induced muscle atrophy in our C26 mouse model (data not shown), the present data suggest that the BMP axis can be an effective target for therapeutic approaches to counteract cachexia also in cancer patients. The results of morphometric and immunohistochemical studies collected till now may suggest that denervation contributes to myofiber atrophy in cancer cachexia.
4
Lauzon, Marc-Antoine. "Modélisation d'un système de libération d'un peptide dérivé de la BMP-9 et étude mécanistique comparative entre la BMP-9 et la BMP-2." Mémoire, Université de Sherbrooke, 2014. http://savoirs.usherbrooke.ca/handle/11143/103.
Abstract:
Le vieillissement croissant de la population canadienne aura une incidence, dans les années à venir, sur les risques de fractures ostéoporotiques et autres pathologies de l'os. Parmi ces risques, les fractures avec pertes osseuses présentent des défis considérables et causent un lourd fardeau économique. La société Ostéoporose Canada estime que plus de 30 milliards de dollars seront dépensés pour le traitement de l’ostéoporose et de leurs fractures associées d’ici 2018. La méthode de comblement des pertes osseuses standard actuelle, soit l'autogreffe, est limitée et présente des risques pour le patient. À titre d'alternative, deux stratégies ont été jusqu'à maintenant étudiées: les systèmes de libération de facteurs de croissance (« growth factor delivery systems », GFDS) et le développement de matériaux biomimétiques. Ces deux stratégies ont comme point commun l'utilisation de facteurs de croissance ostéogéniques comme les protéines morphogénétiques osseuses (BMPs), telles la BMP-2 (référence commerciale) et la BMP-9. Malgré leur effet important, les BMPs restent couteuses à produire. Le laboratoire de N. Faucheux a développé un peptide (pBMP-9) dérivé de la BMP-9 qui possède un effet ostéogénique démontré, mais dont les mécanismes d’action et le comportement en système de libération restent à être étudiés. Les objectifs de ce projet de recherche ont donc porté sur l’étude du comportement de cellules osseuses préostéoblastes murins (MC3T3-E1) face à ces facteurs de croissance ainsi que sur le suivi et la modélisation des cinétiques de libération du pBMP-9 à partir d’une matrice de collagène, utilisée actuellement en clinique. Le mémoire possède ainsi trois volets.
Le premier volet de ces travaux a consisté à faire une revue de la littérature sur le processus de régénération osseuse endochondrale afin de bien comprendre le rôle joué par les facteurs de croissance et cerner les défis de conception d’un GFDS utilisé en régénération osseuse. Les nouvelles approches de GFDS ont été revues en détail ainsi que les principaux modèles mathématiques développés et appliqués aux molécules thérapeutiques. Cette revue de la littérature a été publiée dans Journal of Controlled Release.
Le second volet de ces travaux s’est penché sur l’étude et la modélisation mathématique des cinétiques de libération du pBMP-9 à partir d’hydrogels de collagène. Les résultats expérimentaux ont mené à la rédaction d’un article qui vient d’être accepté dans la revue Journal of Controlled Release. Cette étude consistait à évaluer les mécanismes de transfert de masse impliqués dans la libération pour différentes concentrations de pBMP-9 à partir d'hydrogels de collagène. Les cinétiques de libération ont été modélisées et ont montré la présence d'interactions importantes entre le pBMP-9 et les fibres de collagène.
Le troisième volet a consisté à déterminer l'effet dose de la BMP-9 et de la BMP-2 sur la capacité des MC3T3-E1 à se différencier en présence ou en absence de sérum de veau foetal (« foetal bovine serum », FBS). Ces travaux ont conduit à la rédaction d’un article qui vient d’être accepté dans la revue Tissue Engineering Part A. La BMP-9 étant jusqu'alors mal comprise, l'étude s'est penchée sur cette protéine tout en ayant comme objectif de transposer les connaissances au pBMP-9. Les résultats ont démontré que les mécanismes d'action de la BMP-9 étaient très différents de ceux de la BMP-2 en présence de FBS. Les résultats ont également permis d'établir que, à l'instar de la BMP-2, la présence de FBS potentialise fortement l'effet ostéogénique de la BMP-9. Cet effet a d’ailleurs pu être récréé par l’IGF-2. Les conclusions de ce travail favoriseront le développement de systèmes de libération ostéogéniques plus efficaces.
5
Budde, Christian. "Immunhistochemische Beurteilung von BMP-2 und BMP-4 in der humanen ungestörten und verzögerten Frakturheilung." [S.l.] : [s.n.], 2002. http://deposit.ddb.de/cgi-bin/dokserv?idn=96584630X.
6
Hillger, Frank. "Rekombinante Herstellung und biophysikalische Charakterisierung von proBMP-2, BMP-2 und dem BMP-2-Propeptid." [S.l. : s.n.], 2005. http://deposit.ddb.de/cgi-bin/dokserv?idn=975601210.
7
Kirchhoff, Christina [Verfasser], and Hagen [Akademischer Betreuer] Schmal. "Die Lokalisation von BMP-2, BMP-7 und deren Rezeptoren im Kniegelenk bei umschriebenem Knorpelschaden." Freiburg : Universität, 2014. http://d-nb.info/1122742517/34.
8
Tanaka, Mari. "Expression of BMP-7 and USAG-1 (a BMP antagonist) in kidney development and injury." Kyoto University, 2009. http://hdl.handle.net/2433/124309.
9
Carvalho, Sara Catarina da Silva. "O papel das BMPs na regeneração óssea." Master's thesis, [s.n.], 2015. http://hdl.handle.net/10284/5139.
Abstract:
Projeto de Pós-Graduação/Dissertação apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Mestre em Medicina DentáriaO tecido ósseo quando lesado possui capacidade de regeneração. No entanto, na presença de certas patologias ou lesões, esta capacidade poderá ser comprometida. Neste contexto, a fração de uma proteína foi isolada da matriz óssea desmineralizada, denominando-se Bone Morphogenetic Proteins (BMPs) ou Proteínas Morfogenéticas do Osso; descobertas pelo Dr. Marshall Urist em 1965. Estas proteínas parecem constituir uma boa alternativa no contorno deste problema, uma vez que possuem capacidade de formar cartilagem e novo osso (inclusive osso heterotópico). O seu uso clínico foi aprovado pela Food and Drug Administration (FDA), respetivamente a BMP 7 e BMP 2. Devido ao seu potencial osteoindutivo e osteocondutivo, vários estudos in vitro e in vivo têm decorrido desde a sua descoberta. Sendo que estes fatores tornaram-se de grande interesse em várias áreas como a Ortopedia na Medicina e Cirurgia Oral na Medicina Dentária. Esta revisão bibliográfica tem como intuito o esclarecimento a partir da informação disponível acerca destas proteínas, nomeadamente, a sua constituição, mecanismos de ação, fatores condicionantes e potenciadores da sua ação, aplicações clínicas (inclusive na área da Medicina Dentária) e limitações no seu uso como fator regenerativo. Bone tissue when injured has the ability of regeneration. However, in the presence of certain pathologies or lesions, this ability can be compromised. In this context, a fraction of a protein was isolated from the demineralized bone matrix, called Bone Morphogenetic Proteins (BMPs); discovered by Dr. Marshall Urist in 1965. These proteins appear to be a good alternative to the overcome this problem, as they possess the ability to form new cartilage and bone, even heterotopic bone. Their clinical use was approved by Food and Drug Administration (FDA), respectively BMP 7 and BMP 2. Due to their osteoinductive and osteoconductive potential, several in vitro and in vivo studies have occurred since their discovery. Therefore these factors have become of great interest in various fields such as Orthopedics in Medicine and Oral Surgery in Dentistry. This literature review has the aim to clarify the available information about these proteins, namely, their constitution, mechanisms of action, conditioning factors and enhancers of their action, clinical applications (including in the field of Dentistry) and limitations of their use as a regenerative factor.
10
Krätzig, Matthias [Verfasser]. "Untersuchungen zur Renaturierung und Aufreinigung von BMP-2 und BMP-4 aus Escherichia coli / Matthias Krätzig." Hannover : Technische Informationsbibliothek (TIB), 2016. http://d-nb.info/1097220141/34.
11
Merve, Ashirwad J. "BMI1-BMP connection in medulloblastoma pathogenesis." Thesis, Queen Mary, University of London, 2014. http://qmro.qmul.ac.uk/xmlui/handle/123456789/8304.
Abstract:
Medulloblastoma (MB) is the commonest intracranial childhood malignancy and despite recent advances, current therapeutic approaches are still associated with high morbidity and mortality. A novel molecular classification has recently been proposed for these tumours – WNT Group (best prognosis), SHH Group (intermediate prognosis), Group 3 (worst prognosis) and Group 4 (intermediate prognosis). BMI1, a transcriptional repressor of the Polycomb group genes, is overexpressed in MB, most significantly in those of Group 4 MBs. Bone Morphogenetic Proteins (BMPs) are morphogens belonging to TGF-β superfamily of growth factors, and are known to inhibit MB cell proliferation and induce apoptosis in vitro, and to inhibit tumour growth in vivo. Our team have recently demonstrated that Bmi1 regulates cell adhesion properties during cerebellar development through repression of the BMP pathway. The aim of this project is to assess whether BMI1 overexpression may contribute to MB pathogenesis through repression of the BMP pathway. Here we demonstrate that BMI1 knock down derepresses BMP pathway, and using a novel xenograft model of human MB of Group 4, we show that BMI1 controls tumour volume and intraparenchymal invasion. In in vitro assays on MB cell lines we show that cell adhesion and motility is controlled by BMI1 in a BMP dependent manner and that deregulation of extracellular matrix proteins are key mediators of this effect. Furthermore, we demonstrate that BMP treatment to BMI1 overexpressing MB cells reduces cell proliferation and invasion, suggesting BMI1 as a possible biomarker for those tumours that could benefit from treatment with BMP agonist small molecules.
12
Stantzou, Amalia. "BMP signaling controls postnatal muscle development." Thesis, Paris 6, 2015. http://www.theses.fr/2015PA066337/document.
Abstract:
Les "Bone Morphogenetic Proteins" (BMPs) jouent un rôle clef dans la régulation de cellules précurseurs du muscle prénatal et de cellules souches musculaires adultes dénommées "cellules satellites". Les objectifs principaux de ma thèse étaient d'une part de déterminer si la signalisation BMP joue un rôle pendant la phase de croissance du muscle postnatale/juvénile dépendante des cellules satellites, et d'autre part d'investiguer si cette voie est impliquée dans la maintenance de la masse musculaire squelettique adulte. J'ai trouvé que les composants de cette voie de signalisation sont exprimés dans les cellules satellites de souris néonatales, juvéniles et adultes. Par ailleurs, j'ai utilisé des lignées de souris transgéniques pour surexprimer, de manière conditionnelle, l'inhibiteur Smad6 de la cascade de signalisation BMP dans les cellules satellites ou dans le muscle squelettique. J'ai pu ainsi démontrer que cette signalisation est requise pour une prolifération correcte des cellules satellites et pour leur différentiation en myonuclei, assurant que les fibres musculaires en croissance atteignent une taille finale normale. Par ailleurs, mes travaux révèlent que le nombre final de cellules satellites est établis pendant la phase de croissance postnatale/juvénile et que celle-ci dépend de la cascade de signalisation BMP. Enfin, je fournis des preuves montrant que la signalisation BMP est un puissant signal hypertrophique dans le muscle squelettique adulte et que sa présence est indispensable pour le maintien du tissu musculaire. En résumé, mes résultats de recherche démontrent que les BMPs sont des facteurs de croissance essentiels pour le muscle squelettique postnatalBone Morphogenetic Proteins (BMPs), a subfamily of TGF-β growth factors, have been shown to be key signals that regulate embryonic and fetal muscle precursors during prenatal myogenesis, as well as the stem cells of adult muscle, termed ‘satellite cells’, when activated during muscle regeneration. The main aims of my thesis were to elucidate whether BMP signaling plays a role during postnatal/juvenile satellite cell-dependent muscle growth as well as for maintenance of adult muscle mass. I found that components of BMP signaling pathway are expressed in muscle satellite cells of neonatal, juvenile and adult mice. I used transgenic mouse lines to conditionally overexpress the BMP signaling cascade inhibitor Smad6 in muscle satellite cells and in differentiated skeletal muscle. I show that BMP signaling is required for correct proliferation of muscle satellite cells and their differentiation into myonuclei, thereby ensuring that the growing muscle fibers reach the correct final size. Moreover, I demonstrated that the final number of muscle stem cells is established during the postnatal/juvenile growth phase and this also depends on the BMP signaling cascade. Finally, I provide evidence that BMP signaling is a strong hypertrophic signal for the adult skeletal muscle and its presence is indispensable for muscle tissue maintenance. In summary, my findings demonstrate that BMPs are essential growth factors for postnatal skeletal muscle
13
Baker, Paul B., William B. McCloskey, Will Sherman, and Timothy D. Dennehy. "IPM/BMP Practices in Arizona Cotton." College of Agriculture, University of Arizona (Tucson, AZ), 1998. http://hdl.handle.net/10150/210371.
Abstract:
Arizona cotton growers were surveyed regarding the importance of Integrated Pest Management (IPM) and Best Management Practices (BMP). Telephone surveys reached 249 individuals over a ten-day period. The survey asked growers to rate the importance of each IPM/BMP tactic on a scale of 1 (not important) to 5 (very important). Of the 14 practices /tactics listed for IPM, eight had significant chi-square values. These included scouting, crop rotation, variety selection, petiole testing for nitrogen, pheromone use, equipment calibration, and stalk destruction. Of the eight practices /tactics listed for BMP, six had significant chi -square values. These included crop rotation, timing and splitting of nitrogen applications, petiole testing, time of planting and variety selection for specific suppression (Bt cotton). In general, whether it was an IPM, weed management, or a BMP practice/tactic, the growers scored a majority of the tactics as important. It could be inferred from the growers' responses that they agree that the practices listed as important were, in fact, important grower practices.
14
Simon, Michaela. "Der Einfluss von Bone Morphogenetic Protein (BMP-)2, BMP-4 und BMP-7 auf die Regulation der Proliferation und Differenzierung von hämatopoetischen Vorläuferzellen aus dem peripheren Blut." kostenfrei, 2009. http://www.opus-bayern.de/uni-regensburg/volltexte/2009/1393/.
15
Laflamme, Claude. "Rôle des facteurs de croissance EGF, FGF-2, BMP-2 et BMP-7 dans la régénération osseuse." Thesis, Université Laval, 2012. http://www.theses.ulaval.ca/2012/29050/29050.pdf.
16
Fourel, Laure. "Synergie entre récepteurs BMP et intégrines révélée par la présentation de la BMP-2 par un biomatériau." Thesis, Grenoble, 2012. http://www.theses.fr/2012GRENI109.
Abstract:
La matrice extra-cellulaire lie les facteurs de croissance et régule non seulement leur présentation à la cellule mais aussi leur signalisation. Dans cette thèse, nous employons un film multicouche à base de hyaluronane et de poly(L-lysine) aux propriétés mécaniques modulables afin de mimer la présentation du facteur de croissance BMP-2 telle qu’elle existe dans les conditions physiologiques. Ainsi, ce mode de présentation combiné à l’utilisation d’un substrat mou a révélé des effets drastiques de la BMP-2 sur l’adhésion et la migration de myoblastes à temps court. Le confinement spatial du facteur de croissance permet de potentialiser ses effets en induisant une action synergique entre les récepteurs BMP et les intégrines. En mettant en évidence pour la première fois cette coopération bidirectionnelle, nous montrons qu’elle est nécessaire dans les voies de signalisation de la différenciation osseuse induite par la BMP-2 à travers une réorganisation du cystosquelette médiée par les intégrines b3Extracellular matrix binds growth factors and controls their presentation to the cells but also theirsignaling pathway. In this work, we use a polyelectolyte multilayer film made of a polypeptide andof hyaluronan with tunable mechanical properties to mimic BMP-2 presentation by the matrix.Presentation of matrix-bound BMP-2 reveals so far hidden phenomena on myoblast cell adhesionand migration. The spatial patterning of growth factor leads to maximized effects of growth factorand induces synergy between BMP receptors and integrins. We show that cross-talk between BMP2receptors and b3 integrins is required for genetic program associated with SMAD signaling viareorganization of the cell cytoskeleton
17
Lauzon, Marc-Antoine. "Mod??lisation d'un syst??me de lib??ration d'un peptide d??riv?? de la BMP-9 et ??tude m??canistique comparative entre la BMP-9 et la BMP-2." Mémoire, Universit?? de Sherbrooke, 2014. http://savoirs.usherbrooke.ca/handle/11143/103.
Abstract:
Le vieillissement croissant de la population canadienne aura une incidence, dans les ann??es ?? venir, sur les risques de fractures ost??oporotiques et autres pathologies de l'os. Parmi ces risques, les fractures avec pertes osseuses pr??sentent des d??fis consid??rables et causent un lourd fardeau ??conomique. La soci??t?? Ost??oporose Canada estime que plus de 30 milliards de dollars seront d??pens??s pour le traitement de l???ost??oporose et de leurs fractures associ??es d???ici 2018. La m??thode de comblement des pertes osseuses standard actuelle, soit l'autogreffe, est limit??e et pr??sente des risques pour le patient. ?? titre d'alternative, deux strat??gies ont ??t?? jusqu'?? maintenant ??tudi??es: les syst??mes de lib??ration de facteurs de croissance (?? growth factor delivery systems ??, GFDS) et le d??veloppement de mat??riaux biomim??tiques. Ces deux strat??gies ont comme point commun l'utilisation de facteurs de croissance ost??og??niques comme les prot??ines morphog??n??tiques osseuses (BMPs), telles la BMP-2 (r??f??rence commerciale) et la BMP-9. Malgr?? leur effet important, les BMPs restent couteuses ?? produire. Le laboratoire de N. Faucheux a d??velopp?? un peptide (pBMP-9) d??riv?? de la BMP-9 qui poss??de un effet ost??og??nique d??montr??, mais dont les m??canismes d???action et le comportement en syst??me de lib??ration restent ?? ??tre ??tudi??s. Les objectifs de ce projet de recherche ont donc port?? sur l?????tude du comportement de cellules osseuses pr??ost??oblastes murins (MC3T3-E1) face ?? ces facteurs de croissance ainsi que sur le suivi et la mod??lisation des cin??tiques de lib??ration du pBMP-9 ?? partir d???une matrice de collag??ne, utilis??e actuellement en clinique. Le m??moire poss??de ainsi trois volets.
Le premier volet de ces travaux a consist?? ?? faire une revue de la litt??rature sur le processus de r??g??n??ration osseuse endochondrale afin de bien comprendre le r??le jou?? par les facteurs de croissance et cerner les d??fis de conception d???un GFDS utilis?? en r??g??n??ration osseuse. Les nouvelles approches de GFDS ont ??t?? revues en d??tail ainsi que les principaux mod??les math??matiques d??velopp??s et appliqu??s aux mol??cules th??rapeutiques. Cette revue de la litt??rature a ??t?? publi??e dans Journal of Controlled Release.
Le second volet de ces travaux s???est pench?? sur l?????tude et la mod??lisation math??matique des cin??tiques de lib??ration du pBMP-9 ?? partir d???hydrogels de collag??ne. Les r??sultats exp??rimentaux ont men?? ?? la r??daction d???un article qui vient d?????tre accept?? dans la revue Journal of Controlled Release. Cette ??tude consistait ?? ??valuer les m??canismes de transfert de masse impliqu??s dans la lib??ration pour diff??rentes concentrations de pBMP-9 ?? partir d'hydrogels de collag??ne. Les cin??tiques de lib??ration ont ??t?? mod??lis??es et ont montr?? la pr??sence d'interactions importantes entre le pBMP-9 et les fibres de collag??ne.
Le troisi??me volet a consist?? ?? d??terminer l'effet dose de la BMP-9 et de la BMP-2 sur la capacit?? des MC3T3-E1 ?? se diff??rencier en pr??sence ou en absence de s??rum de veau foetal (?? foetal bovine serum ??, FBS). Ces travaux ont conduit ?? la r??daction d???un article qui vient d?????tre accept?? dans la revue Tissue Engineering Part A. La BMP-9 ??tant jusqu'alors mal comprise, l'??tude s'est pench??e sur cette prot??ine tout en ayant comme objectif de transposer les connaissances au pBMP-9. Les r??sultats ont d??montr?? que les m??canismes d'action de la BMP-9 ??taient tr??s diff??rents de ceux de la BMP-2 en pr??sence de FBS. Les r??sultats ont ??galement permis d'??tablir que, ?? l'instar de la BMP-2, la pr??sence de FBS potentialise fortement l'effet ost??og??nique de la BMP-9. Cet effet a d???ailleurs pu ??tre r??cr???? par l???IGF-2. Les conclusions de ce travail favoriseront le d??veloppement de syst??mes de lib??ration ost??og??niques plus efficaces.
18
Zhou, Lixiong, and 周立雄. "Differential action of bone morphogenetic protein BMP-2 and BMP-7 on nucleus pulposus cells of intervertebral disc." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2014. http://hdl.handle.net/10722/209509.
Abstract:
Low back pain (LBP) is associated with intervertebral disc (IVD) degeneration and exerts enormous socioeconomic burdens on the society. The nucleus pulposus (NP) is the structural and functional core of the IVD, and plays vital roles in its homeostasis. Although the etiology of IVD degeneration is not fully understood, the cellular changes of the NP have been proposed to be associated with degeneration. Conventional management for IVD degeneration primarily targets to relieve LBP and other symptoms without restoring or preserving disc function. Novel therapeutic strategies have emerged with an aim to retard or even reverse disc degeneration. In particular, the use of growth factors, such as the bone morphogenetic proteins (BMP), has received considerable attention due to their anabolic effects on extracellular matrix (ECM) synthesis by NP cells.
BMP-2 and BMP-7 are of great interest for their involvement in osteogenesis, chondrogenesis, and development and maintenance of the IVD. To date, the benefits of BMP-2 on disc degeneration are controversial, given the inconsistent findings from animal model studies. The effectiveness of BMP-7 in disc repair, however, has been well demonstrated both in vitro and in vivo. A better understanding of the differences between BMP-2 and BMP-7 regulatory action on NP cells may facilitate future applications of BMP in disc repair/regeneration.
This study hypothesized that BMP-2 and BMP-7 act differentially on human NP cells via different signal transduction processes. The differential effect of BMP-2 and BMP-7 was first tested in bovine NP cells using a three-dimensional culture system (alginate beads). Both BMP-2 and BMP-7 enhanced ECM production and phenotypic characteristics of bovine NP cells. Notably, BMP-7 was significantly more potent than BMP-2 in this regard. The effects of BMPs were further tested on non-degenerated (ND-NP) and degenerated (D-NP) human NP cells. The DMMB assay revealed that BMP-7 exerted a superior up-regulatory action on GAG production of D-NP cells compared to BMP-2. Furthermore, the overall response of D-NP cells to BMP-2 and BMP-7 was significantly lower than ND-NP cells.
Immunohistochemical staining and quantitative RT-PCR assays demonstrated that D-NP cells possess a more fibroblastic and less chondrocyte-like phenotype than ND-NP cells. At the mRNA level, the BMP receptor BMPR1A was not expressed in D-NP cells. BMP-7, but not BMP-2, induced expression of BMPR1A in D-NP cells. On the other hand, gene expression of selected TGF-β pathway components and hypoxia pathway components were significantly up-regulated by BMP-2 but down-regulated by BMP-7. These findings suggest that D-NP cells can activate differential molecular cascades in response to BMP-2 and BMP-7.
In conclusion, this study showed a superior effect of BMP7 in up-regulation of classical BMP signaling components including BMP receptor BMPR1A. The reduced responsiveness of D-NP cells to BMP-2 and BMP-7 stimulation may be related to a different expression pattern of BMP receptors. This study provides insights into the differential regulatory actions of BMP-2 and BMP-7 on human NP cells and facilitates the future application of BMPs in managing disc degeneration.published_or_final_version
Orthopaedics and Traumatology
Doctoral
Doctor of Philosophy
19
Esser, Marcel [Verfasser]. "Charakterisierung des BMP-7 Signalwegs und der TGF-beta1/BMP-7 Wechselwirkungen in Myofibroblasten-ähnlichen Zellen / Marcel Esser." Aachen : Hochschulbibliothek der Rheinisch-Westfälischen Technischen Hochschule Aachen, 2011. http://d-nb.info/1018224211/34.
20
Ossege, Stephanie. "Charakterisierung BMP-2-stimulierter Calvarienzellen immunhistochemische Untersuchungen /." [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=972836225.
21
Bennett, Louise Agnes. "BMP-7 : role and regulation in osteoarthritis." Thesis, University of Glasgow, 2017. http://theses.gla.ac.uk/8171/.
Abstract:
Osteoarthritis (OA) is a disease characterised by changes in the structure and function of articular joints, leading to pain and loss of mobility. Bone Morphogenetic protein 7 (BMP-7), a member of the transforming growth factor β superfamily, has been shown to promote anabolic events within articular cartilage, and confer protection from OA associated destruction in a number of animal models. It has been shown that a disease-associated loss of BMP-7 in OA may contribute to the joint destruction. The mechanism associated with the loss of BMP-7 has yet to be fully elucidated. Recently, small non-coding RNAs (microRNAs) that participate in post-transcriptional gene regulation, have been identified as a potential dysregulated mechanisms in OA. It was therefore hypothesised that disease-associated alterations in these microRNAs could lead to subsequent changes in the expression of BMP-7 and its signalling family. The aims of this thesis were to investigate the expression of BMP-7 and other associated BMP signalling molecules and identify any microRNAs that may regulate these transcripts. Furthermore, the study aimed to elucidate the molecular mechanisms by which BMP-7 is able to confer protection in cartilage. The studies presented in this thesis show that both articular chondrocytes and the synovial membrane can express very low levels of BMP-7 transcript in a subset of patients. In juxtaposition, protein can be clearly detected in both articular chondrocytes and synovial membrane. Interrogation of the BMP-7 signalling family transcripts revealed that all members are detectable in OA cartilage. This expression was independent of the eroded nature of the cartilage. Evaluation of the circulating microRNAs that were predicted to target the BMP-7 pathway revealed that several miRNAs (including miR24-3p) were altered in the plasma of OA patients. Interestingly, miR24-3p was able to target BMP receptors ALK2 and BMPR1B. Moreover, there was a significant negative correlation between the expression of miR24-3p and the ALK2 receptor in OA patients. Thus suggesting there is a role for this miRNA in the negative regulation of BMP-7 signalling in OA cartilage. To complement the work evaluating the endogenous signalling pathway, studies were also undertaken to investigate the impact of exogenous BMP-7 stimulation on chondrocytes. BMP-7 was able to promote its own transcriptional expression in a patient specific manner and induce expression of IL-1β in all of the donors investigated. In addition to the induction of IL-1β, BMP-7 was also able to up-regulated the IL-1β antagonist, IL-1Ra. Taken together this data suggests a role for BMP-7 in the regulation of the inflammatory mediator IL-1β. Finally, BMP-7 was able to up-regulate several pro-inflammatory cytokines and chemokines in both primary OA chondrocytes and in vitro differentiated macrophages. In summation, the work presented in this thesis suggests that BMP-7 may be contributing to the promotion of inflammation and subsequent repair as part of the cartilage homeostatic mechanisms. Further to this, miR24 has been highlighted as a regulator of cartilage homeostasis via the direct targeting of ALK2. Changes in the expression of this miRNA over the course of OA disease progression may be involved in driving disease pathogenesis. Therefore understanding the targets for this disease-associated miRNA may help in the development of disease modifying therapies.
22
Weber, Dionys A. "Aufklärung der Struktur und Charakterisierung des ternären Komplexes aus BMP-2, BMPR-IA und ActR-IIB." [S.l.] : [s.n.], 2006. http://deposit.ddb.de/cgi-bin/dokserv?idn=982568614.
23
Kotzsch, Alexander. "BMP Ligand-Rezeptor-Komplexe : Molekulare Erkennung am Beispiel der Spezifischen Interaktion zwischen GDF-5 und BMPR-IB." Doctoral thesis, kostenfrei, 2008. http://www.opus-bayern.de/uni-wuerzburg/volltexte/2008/3104/.
24
MacKay, Robin. "Beneficial management practice (BMP) adoption by Canadian producers." Thesis, McGill University, 2010. http://digitool.Library.McGill.CA:8881/R/?func=dbin-jump-full&object_id=92370.
25
Althini, Susanna. "Experimental Studies of BMP Signalling in Neuronal Cells." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis Univ.-bibl. [distributör], 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3398.
26
Stantzou, Amalia [Verfasser]. "BMP signaling controls postnatal muscle development. / Amalia Stantzou." Berlin : Freie Universität Berlin, 2016. http://d-nb.info/1115184202/34.
27
Sieber, Christina [Verfasser]. "Characterization of a BMP co-receptor / Christina Sieber." Berlin : Freie Universität Berlin, 2010. http://d-nb.info/1024334643/34.
28
Meiklejohn, Stuart J. "The role of BMP signalling in HSC ontogeny." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:305597a8-b8cb-42ff-88fd-34b3dd5bf39b.
Abstract:
The haematopoietic stem cell (HSC) is found in the adult human bone marrow, where it gives rise to all the circulating blood cells throughout adulthood. Understanding the signalling events that programme these cells during development will improve HSC in vitro culture, their generation from embryonic stem cells or induced pluripotent stem cells, and their potential therapeutic application. HSCs bud from the floor of the dorsal aorta and seed the bone marrow via circulation. The precursors to the dorsal aorta and HSCs are called haemangioblasts, which are found in the dorsal lateral plate mesoderm in Xenopus. The knowledge of the location of these precursors allows their programming to be studied in detail during embryonic development. A key pathway implicated in the programming of HSCs is the BMP signalling pathway. Here, using both a small molecule inhibitor and a transgenic Xenopus line, BMP signalling has been inhibited post-gastrulation without perturbing the gross morphology of the embryo. This has shown that BMP signalling is required for HSC programming in the dorsal lateral plate mesoderm via the expression of a critical haematopoietic transcription factor, gata2. Morpholino knockdown of evi3has revealed it to be essential for HSC programming in the dorsal lateral plate mesoderm, where it is required for the expression of gata2. Furthermore, as evi3 is known to bind to the active BMP signalling complex, and as evi3 knockdown phenocopies post-gastrulation BMP inhibition, evi3 appears to be required for BMP signalling to initiate gata2 expression in the DLP. Taken together, the findings presented here demonstrate an essential post-gastrulation role of BMP signalling and Evi3 for programming HSCs in Xenopus.
29
Costa, Carla Christina Rodrigues. "BMP (Bone Morphogenetic Protein) : uma abordagem terapêutica inovadora." Universidade de Taubaté, 2008. http://www.bdtd.unitau.br/tedesimplificado/tde_busca/arquivo.php?codArquivo=459.
Abstract:
A odontologia, atualmente, conta com uma nova abordagem terapêutica no campo da regeneração tecidual. Essa abordagem baseia-se no uso de moléculas bioativas, mais especificamente as BMPs (Bone Morphogenetic Proteins). A presente revisão propõe-se a apresentar alguns relatos, existentes na literatura, do uso das BMPs como medicamento, dando embasamento para realização de novos experimentos que possam sugerir abordagens terapêuticas inovadoras na área da regeneração tecidual. As BMPs são proteínas pleiotrópicas, que estão envolvidas no desenvolvimento de vários órgãos do corpo humano, e, também, estão presentes nas várias fases da morfogênese dentária, controlando e modulando as atividades celulares. As BMPs têm o potencial de serem usadas, tanto para a regeneração do complexo dentina-polpa quanto para a regeneração do periodonto (osso, cemento, ligamento, gengiva), podem ser empregadas em cirurgias craniofacial para correção de anomalias adquiridas ou herdadas, correção de seqüelas de trauma craniano, seqüelas de câncer, defeitos ósseos e reparo da cartilagem têmporomandibular. Deste trabalho pode-se concluir que a BMP: (1) tem importância na regeneração tecidual como elemento chave na engenharia de tecido; (2) oferece a vantagem de ser uma abordagem mais biológica, gerando um tecido idêntico ao perdido; (3) tem sido bem estudada em vários experimentos clínicos, com muito sucesso, inclusive em humanos; e (4) poderá estar disponível como uma alternativa de terapia a ser empregada no consultório odontológico.Nowadays, odontology counts on a new therapeutic approach in the field of tissue regeneration. This approach is based in the use of bioactive molecules, specifically the BMPs (Bone Morphogenetic Proteins). The present revision has in view to know the BMPs and its applications as medicines, offering support to the accomplishment of experiments that could suggest new proposes of treatment in the field of tissue regeneration. The BMPs are pleiotropic proteins that are involved in the development of many organs of the human body and they are also present in the several phases of dental morphogenesis, controlling and modulating the cellular activities. The BMPs have the potential to be used to the regeneration of the dentin-pulp complex as much as to the regeneration of the periodontium (bone, cementum, ligament and gingiva), and can be used in facial and cranial surgeries to the correction of acquired or inherited anomalies, correction of cranial trauma consequences, bone defects and repair of the temporal- mandible cartilage. From this review, we can conclude some topics about the BMP: (1) it has importance in the tissue regeneration as a key element in tissue engineering; (2) the BMP offers the advantage of being a more biologic approach, generating a new tissue that is identic to the lost one; (3) it has been studied in several clinic experiments, with great success, even including humans; (4) it probably will be available as an alternative of therapy, that may be used in odontologic rooms in the future.
30
Gutierrez, Christian. "The BMP pathway its role in retina regeneration /." Oxford, Ohio : Miami University, 2008. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=miami1228837408.
31
Yamada, Sachiko. "Twisted Gastrulation, a BMP Antagonist, Exacerbates Podocyte Injury." Kyoto University, 2019. http://hdl.handle.net/2433/242348.
32
Young, Kevin D. "Application of the Analytic Hierarchy Process Optimization Algorithm in Best Management Practice Selection." Thesis, Virginia Tech, 2006. http://hdl.handle.net/10919/33815.
Abstract:
The efficiency of a best management practice (BMP) is defined simply as a measure of how well the practice or series of practices removes targeted pollutants. While this concept is relatively simple, mathematical attempts to quantify BMP efficiency are numerous and complex. Intuitively, the pollutant removal capability of a BMP should be fundamental to the BMP selection process. However, as evidenced by the absence of removal efficiency as an influential criterion in many BMP selection procedures, it is typically not at the forefront of the BMP selection and design process.
Additionally, of particular interest to any developer or municipal agency is the financial impact of implementing a BMP. Not only does the implementation cost exist, but there are long-term maintenance costs associated with almost any BMP. Much like pollutant removal efficiency, implementation and maintenance costs seem as though they should be integral considerations in the BMP selection process. However, selection flow charts and matrices employed by many localities neglect these considerations.
Among the categories of criteria to consider in selecting a BMP for a particular site or objective are site-specific characteristics; local, state, and federal ordinances; and implementation and long-term maintenance costs. A consideration such as long-term maintenance cost may manifest itself in a very subjective fashion during the selection process. For example, a BMPs cost may be of very limited interest to the reviewing locality, whereas cost may be the dominant selection criterion in the eyes of a developer. By contrast, the pollutant removal efficiency of a BMP may be necessarily prioritized in the selection process because of the required adherence to governing legislation. These are merely two possible criteria influencing selection. As more and more selection criteria are considered, the task of objectively and optimally selecting a BMP becomes increasingly complex. One mathematical approach for optimization in the face of multiple influential criteria is the Analytic Hierarchy Process. â The analytic hierarchy process (AHP) provides the objective mathematics to process the inescapably subjective and personal preferences of an individual or a group in making a decisionâ (Schmoldt, 2001, pg. 15).
This paper details the development of two categories of comprehensive BMP selection matrices expressing long-term pollutant removal performance and annual maintenance and operations cost respectively. Additionally, the AHP is applied in multiple scenarios to demonstrate the optimized selection of a single BMP among multiple competing BMP alternatives. Pairwise rankings of competing BMP alternatives are founded on a detailed literature review of the most popular BMPs presently implemented throughout the United States.Master of Science
33
Soares, Andrea Ferreira. "Avaliação da expressão da BMP -2/4 e BMPR-IA em Carcinoma Epidermóide Oral metastático e não metastático." reponame:Repositório Institucional da UFS, 2007. https://ri.ufs.br/handle/riufs/1115.
Abstract:
A expressão das proteínas morfogenéticas ósseas (BMPs) está alterada em vários cânceres humanos. A BMP-2/4 e o BMPR-IA foram recentemente encontrados superexpressos em lesões malignas e pré-malignas de alto risco em epitélio oral. Este estudo analisou a expressão da BMP-2/4 e seu receptor BMPR-IA em 23 espécimes de Carcinoma Epidermóide Oral (CEO), utilizando a imuno-histoquímica. O grupo controle constou de 10 casos de Hiperplasia Fibro-epitelial da mucosa oral. O grupo experimental foi constituído por 16 casos de CEO não metastático e 7 casos de CEO metastático. Utilizou-se o parâmetro presença ou ausência de metástase nodal para avaliar o prognóstico da doença. Os resultados demonstraram imunorreatividade fraca para a BMP-2/4 e o BMPR-IA em todos os espécimes do grupo controle. No grupo experimental com metástase, a BMP-2/4 exibiu forte expressividade (71,4%), enquanto que o BMPR-IA mostrou fraca expressão (85,7%). No grupo experimental sem metástase, evidenciou-se forte expressão para a BMP-2/4 (62,5%) e para o BMPR-IA (100%). Encontrou-se significância estatística para a associação entre o prognóstico do CEO e a intensidade de marcação da BMP-2/4 (p=0,002). Para o BMPR-IA não houve significância estatística à sua associação com o prognóstico da doença (p>0,001), em função do tamanho da amostra. Portanto, os resultados sugerem que a fraca expressividade do BMPR-IA associada à forte expressão da BMP-2/4, no grupo experimental com metástase, tem relevância prognóstica, já que a perda de sensibilidade às BMPs, através da perda de expressão de seus receptores pode ser indicativo de desenvolvimento de metástase em CEO. _________________________________________________________________________________________ ABSTRACT: The expression of bone morphogenetic proteins (BMPs) is altered in a variety of human canceres. The BMP-2/4 and BMPR-IA were recently shown to be overexpressed in high-risk premalignant and malignant lesions of oral epithelium. The present study analysed the expression of BMP-2/4 and BMPR-IA in Oral Squamous Cell Carcinoma (OSCC) such as their implications in disease prognostic using munohistochemistry. Ten cases of Oral Fibroepithelial Hiperplasia were selected as a control group. The experimental group included 16 cases of OSCC without metastases and 7 cases of OSCC metastatic. The presence or absence of nodal metastases was used as parameter to evaluated the disease prognostic. The results demonstrated weak immunoreactivity for BMP-2/4 and BMPR-IA in every case of the control group. In the cases of OSCC with metastases an overexpression of BMP-2/4 (71,4%) was observed while the BMPR-IA showed weak expression (85,7%). In the cases of OSCC without metastases BMP-2/4 (62,5%) and BMPR-IA showed strong immunostaining standing out an overexpression of the receptor in all the specimens. Observed statistical significance for correlation between the oral cancer prognostic and the staining intensity of the BMP-2/4 (p=0,002). There wasn t statistical significance for association between the staining intensity of the BMPR-IA and the disease prognostic (p>0,001). In conclusion, this findings suggest that the overexpression of BMP-2/4 associated with the loss of expression of the BMPR-IA in OSCC metastatic has prognostic relevance, as the loss of sensitivity to BMPs can be an indicative of metastases development in OSCC.
34
Gamell, Fullà Cristina. "Regulació de la migració cel·lular induïda per BMP-2." Doctoral thesis, Universitat de Barcelona, 2009. http://hdl.handle.net/10803/1166.
Abstract:
EN CATALÀ :Les proteïnes morfogenètiques òssies (BMPs) són membres de la superfamília del TGF-beta i s'ha demostrat que participen en la determinació i especificació de varis teixits i òrgans durant el desenvolupament dels vertebrats i que regulen la proliferació, l'apoptosi i la diferenciació de múltiples tipus cel·lulars. Les BMPs van ser originàriament identificades per a la seva habilitat d'induir la formació ectòpica d'os i entre ells, BMP-2, -4 and -7 resulten essencials perquè tingui lloc un adequat desenvolupament ossi. Les BMPs també s'ha descrit que participen en el control de la migració cel·lular durant la morfogènesis embrionària. Malgrat s'han publicat alguns treballs en relació a la participació de BMPs en la regulació de la migració de progenitors mesenquimals i osteoblasts, els mecanismes moleculars mitjançant els quals les BMPs regulen aquests processos són poc coneguts. Tenint en compte aquests precedents, ens varem proposar estudiar la participació de BMP-2 en la regulació de la migració de les cèl·lules mioblàstiques C2C12.
Els resultats presentats en aquest treball demostren que BMP-2 indueix la migració cel·lular quimiotàctica en cèl·lules C2C12. Les evidències experimentals que ens permeten arribar a aquesta conclusió són: i) l'anàlisi de la migració cel·lular mitjançant l'assaig de ferida indica que en presència de BMP-2 la ferida és repoblada més eficientment i que aquest efecte és independent de la síntesis proteica de novo i de la proliferació cel·lular; ii) els resultats obtinguts en l'aproximació experimental basada en l'ús de la Càmera de Boyden mostren que la migració induïda per BMP-2 té caràcter quimiotàctic a favor de gradient de concentració. Tenint en compte que la resposta inicial de la cèl·lula a un agent quimiotàctic consisteix en la polarització i extensió de protrusions en la direcció de la migració, es va analitzar posteriorment l'efecte de BMP-2 en la organització del citoesquelet d'actina. El resultats mostraven que BMP-2 induïa la formació d'acumulacions d'actina cortical, i que es tractava d'un efecte ràpid, transitori i que tenia lloc en diferents tipus cel·lulars, independentment de la distribució basal dels seus filaments d'actina. En relació a l'estudi dels mecanismes moleculars implicats en els efectes de BMP-2 en la dinàmica del citoesquelet d'actina i la migració cel·lular, els resultats obtinguts demostren que BMP-2 regula aquests efectes a través de l'activació de vies de senyalització que involucren Cdc42, PI3K i p38MAPK, que estan implicades en la regulació de proteïnes que tenen un impacte directe sobre la polimerització d'actina. Concretament, BMP-2 indueix l'activació de Cdc42 i la isoforma α de PI3K de manera paral·lela i independent, i ambdues rutes estan implicades en la regulació de l'activitat de varis membres de la família de proteïnes PAK, que alhora regulen la LIMK1, proteïna implicada en el control de la polimerització dels filaments d'actina a través de la fosforilació de la cofilina. Per altra banda, l'activitat de la MAPK p38α també resulta imprescindible en la regulació de la dinàmica del citoesquelet d'actina i la migració cel·lular dependent de BMP-2, a través d'una via de senyalització que involucra la quinasa MK2 i hsp27, proteïna que té la capacitat de regular directament la polimerització dels filaments d'actina. En conjunt, les dades presentades suggereixen noves vies de senyalització activades en resposta BMP-2 que relacionen els receptors de membrana amb la dinàmica del citoesquelet d'actina i la migració cel·lular.
The main focus of the research is to study in depth the effects of Bone Morphogenetic Protein 2 (BMP-2) in the actin cytoskeleton reorganization and cell migration, as well as the study of the signalling pathways implicated in these effects.
BMPs have been shown to participate in the patterning and specification of several tissues and organs during vertebrate development and to regulate cell growth, apoptosis and differentiation in different cell types. We have reported that exposure of C2C12 cells to BMP-2 leads to an increase in cell migration and a rapid rearrangement of the actin filaments into cortical protrusions. These effects required independent and parallel activation of the Cdc42 small GTPase, the α-isoform of the PI3K and the p38α MAPK. Furthermore, we demonstrate that BMP-2 activates different group I and II PAK isoforms as well as LIMK1, and that these activations measured by either kinase activity or with antibodies against phosphorylations at their activation loops, were abolished by blocking PI3K and Cdc42 signalling pathways. Moreover, we have described that BMP-2 induces MK2 and hsp27 activation in a p38-dependent manner and that both proteins are implicated in the effects of BMP-2 on cell migration. Altogether, these findings suggest that Cdc42, PI3K and p38 signals emanated from BMP receptors are involved into specific regulation of actin assembly and cell migration. We are at the moment studying the possible relationship between Cdc42/PI3K-PAK-LIMK1 and p38-MK2-hsp27 pathways. Preliminary results suggest that these pathways are independent; however we are still working on it.
35
Jacob, Eva. "In-vivo-Testung eines neuartigen BMP-2-TCP-Composite." Giessen VVB Laufersweiler, 2006. http://d-nb.info/100049599X/34.
36
Johnson, Mela Ronelle. "Delivery of BMP-2 for bone tissue engineering applications." Diss., Georgia Institute of Technology, 2010. http://hdl.handle.net/1853/33830.
Abstract:
Bone defects and fracture non-unions remain a substantial challenge for clinicians due to a high occurrence of delayed union or non-union requiring surgical intervention. The current grafting procedures used to treat these injuries have many limitations and further long-term complications associated with them. This has resulted in research efforts to identify graft substitution therapies that are able to repair and replace tissue function. Many of these tissue engineered products include the use of growth factors to induce cell differentiation, migration, proliferation, and/or matrix production. However, current growth factor delivery methods are limited by poor retention of growth factors upon implantation resulting in low bioactivity. These limiting factors lead to the use of high doses and frequent injections, putting the patients at risk for adverse effects.
The goal of this work was to develop and evaluate the efficacy of BMP-2 delivery systems to improve bone regeneration. We examined two approaches for delivery of BMP-2 in this work. First, we evaluated the use of a self-assembling lipid microtube system for the sustained delivery of BMP-2. We determined that sustained delivery of BMP-2 from the lipid microtube system was able to enhance osteogenic differentiation compared to empty microtubes, however did not demonstrate a significant advantage compared to a bolus BMP-2 dose in vitro. Second, we developed and assessed the functionality of an affinity-based system to sequester BMP-2 at the implant site and retain bioactivity by incorporating heparin within a collagen matrix. Incorporation of heparin in the collagen matrix improved BMP-2 retention and bioactivity, thus enhancing cell-mediated mineralized matrix deposition in vitro. Lastly, the affinity-based BMP-2 delivery system was evaluated in a challenging in vivo bone repair model. Delivery of pre-bound BMP-2 and heparin in a collagen matrix resulted in new bone formation with mechanical properties not significantly different to those of intact bone. Whereas delivery of BMP-2 in collagen or collagen/heparin matrices had similar volumes of regenerated mineralized tissue but resulted in mechanical properties significantly less than intact bone properties.
The work presented in this thesis aimed to address parameters currently preventing optimal performance of protein therapies including stability, duration of exposure, and localization at the treatment site. We were able to demonstrate that sustained delivery of BMP-2 from lipid microtubes was able to induce osteogenic differentiation, although this sustained delivery approach was not significantly advantageous over a bolus dose. Additionally, we demonstrated that the affinity-based system was able to improve BMP-2 retention within the scaffold and in vitro activity. However, in vivo implantation of this system demonstrated that only delivery of pre-complexed BMP-2 and heparin resulted in regeneration of bone with mechanical properties not significantly different from intact bone. These results indicate that delivery of BMP-2 and heparin may be an advantageous strategy for clinically challenging bone defects.
37
Goulley, Joan. "Role of BMP signaling and ASNA1 in β-cells." Doctoral thesis, Umeå universitet, Umeå centrum för molekylär medicin (UCMM), 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-1810.
Abstract:
Patients with type II diabetes present alterations in glucose homeostasis due to insufficient amount of insulin (β-cell dysfunction) and inability to properly use the insulin that is secreted (insulin resistance). Combined genetical and environmental factors are believed to be responsible for these dysfunctions and the resulting impairment in glucose homeostasis. The pancreatic gland is composed of exocrine and endocrine tissues. The endocrine part of the organ couples glucose sensing to insulin release. Within this endocrine gland, also known as islets of Langerhans, the insulin secreting β-cell is the main player and therefore highly important for proper glucose metabolism. In this thesis, mice were developed in order to assess the role of BMP signaling molecule and Arsenite induced ATPase-1 (Asna1) for pancreas development and β-cell function. The mature β-cell responds to elevated glucose levels by secreting insulin in a tightly controlled manner. This physiological response of the β-cell to elevated blood glucose levels is critical for maintenance of normoglycaemia and impaired Glucose stimulated insulin secretion (GSIS) is a prominent feature of overt type 2 diabetes. Thus, the identification of signals and pathways that ensure and stimulate GSIS in β-cells is of great clinical interest. Here we show (Paper I) that BMPRIA and its high affinity ligand BMP4 are expressed in fetal and adult islets. We also provide evidence that BMPRIA signaling in adult β-cell is required for GSIS, and that both transgenic expression of Bmp4 in β-cells or systemic administration of BMP4 protein to mice enhances GSIS. Thus, BMP4-BMPRIA signaling in β-cells positively regulates the genetic machinery that ensures GSIS. Arsenite induced ATPase (Asna1), the homologue of the bacterial ArsA ATPase, is expressed in insulin producing cells of both mammals and the nematode Caenorhabditis elegans (C.elegans). Asna1 has been proposed to act as an evolutionary conserved regulator of insulin/insulin like factor signaling. In C.elegans, asna-1 has been shown to regulate growth in a non-cell autonomous and IGF-receptor dependent manner. Here we show that transgenic expression of ASNA1 in β-cells of mice leads to enhanced Aktactivity and β-cell hyperplasia (manuscript). ASNA1 transgenic mice develop, however, diabetes due to impaired insulin secretion. The expression of genes involved in secretion stimulus coupling and insulin exocytosis is perturbed in islets of these mice. These data suggest that activation of ASNA1, here mimicked by enhanced expression, positively influences β-cell mass but negatively affects insulin secretion.
38
Kisiel, Marta. "Bone Enhancement with BMP-2 for Safe Clinical Translation." Doctoral thesis, Uppsala universitet, Polymerkemi, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-188027.
Abstract:
Bone morphogenetic protein-2 (BMP-2) is considered a promising adjuvant for the treatment of bone regeneration. However, BMP-2 delivery in a conventional collagen scaffold needs a high dose to achieve an effective outcome. Moreover, such dosage may lead to serious side effects. The aim of the following thesis was to find clinically acceptable strategies reducing the required dose of BMP-2 by improving the delivery and optimizing the preclinical testing of the new approaches. In all the studies hyaluronic acid (HA) hydrogels was used as a carrier for BMP-2. The HA hydrogel/BMP-2 construct was modified with bioactive matrix components in order to obtain an effective release of BMP-2 and an enhanced bone formation. The most promising were two strategies. In the first one, BMP-2, precomplexed with the glycosaminoglycans dermatan sulfate or heparin prior to loading it into HA hydrogel, protected and prolonged the delivery of the protein, resulting in twofold larger bone formation in comparison to non-complexed BMP-2. In the second strategy, the fibronectin fragment integrin-binding domain (FN) was covalently incorporated into HA hydrogel. The FN remarkably improved the capacity of the material to support the cells attachment and spreading, providing the formation of twice as much bone in comparison to non-functionalized HA hydrogel/BMP-2. Furthermore, the importance of a proper design of the preclinical study for BMP-2 delivery systems was highlighted. Firstly, proper physicochemical handling of BMP-2 showed the improvement in further in vivo activity. The use of glass storage vials and an acidic formulation buffer was superior to plastic surfaces and physiological pH. Secondly, while regenerative medicine strategy testing required the use of animal models that matched the research questions related to clinical translation, two new animal models were developed. The subperiosteal mandibular and calvarial models in rats were found to be minimally invasive, convenient and rapid solution for the evaluation of a broad range of approaches including bone augmentation, replacement and regeneration. Both models are primarily relevant for the initial testing of the injectable bone engineering constructs. Those clinically translatable approaches presented here could prove to be a powerful platform for a wider use of BMP-2 in orthopedic, plastic surgery and regenerative medicine research.
39
Hilliard, Randall K. "ORIENTATION-SPECIFIC IMMOBILIZATION OF BMP-2 ON PLGA SCAFFOLDS." UKnowledge, 2007. http://uknowledge.uky.edu/gradschool_theses/463.
Abstract:
A variety of synthetic bone graft materials such as the polymer poly(lactic-co-glycolic acid) (PLGA) have been investigated as alternatives to current tissue based bone graft materials. In this study, efforts have been made to improve the tissue-PLGA interface by immobilizing bone morphogenetic protein-2 (BMP-2) in an oriented manner on scaffolds using covalently immobilized heparin. The results demonstrated a four-fold increase in covalently immobilized heparin compared to non-specific heparin attachment. Furthermore, the scaffolds with covalently attached heparin retained approximately three-fold more BMP-2 than did either scaffolds with no heparin attached or scaffolds with non-specific heparin attachment. The activity of scaffolds with BMP-2 immobilized in various manners was examined using an alkaline phosphatase assay on C3H10T1/2-seeded scaffolds. These results indicated approximately twice the amount of activity with scaffolds that had BMP-2 immobilized with covalently attached heparin than on scaffolds with adsorption of BMP-2 and a three-fold increase in activity when compared to scaffolds that had non-specific heparin attachment as the mechanism for BMP-2 immobilization. These results demonstrated that PLGA with covalently linked heparin has potential to immobilize BMP-2 in a specific orientation that is favorable for cell-receptor binding, leading to the more efficient use of the bone-growth factor.
40
Bogardi, Jean-Philippe Achmed Alfred Töhütöm. "BMP 4 and FGF 8 signalling in maxillary development." Thesis, King's College London (University of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.249250.
41
Deignan, Lisa. "Genomic analyses of BMP signalling-responsive transcription in Drosophila." Thesis, University of Manchester, 2014. https://www.research.manchester.ac.uk/portal/en/theses/genomic-analyses-of-bmp-signallingresponsive-transcription-in-drosophila(7cf265fc-8615-4a5b-a135-bbd5c915ac2f).html.
Abstract:
Bone Morphogenetic Protein (BMP) signalling is an evolutionary conserved pathway, which functions to regulate numerous developmental processes such as cell fate determination and cellular proliferation. In Drosophila melanogaster, the ortholog of the vertebrate BMP2/4 is Decapentaplegic (Dpp). The most extensively characterised role of Dpp signalling in Drosophila is embryonic Dorsal-Ventral patterning. In this developmental environment, the Dpp morphogen acts as a step gradient to specify different concentration thresholds for target gene activation. The resulting nested domains of target gene expression in the embryo cooperate to induce the formation and subsequent maintenance of a simple extra-embryonic tissue, the amnioserosa. The amnioserosa tissue acts as an ideal model tissue to study Dpp-regulated differentiation. This study aims to identify and validate new targets of Dpp signalling, which are required for determining cell fate and differentiation of the amnioserosa tissue during embryogenesis. Additionally, this study aims to identify new regulators of the core signalling pathway. The work presented here was performed using a two tiered approach to understand in more detail the processes that regulate BMP-responsive transcription and the downstream effects. Firstly, RNA-Sequencing was performed on embryos with ectopic Dpp signalling in the early embryo. BMP-responsive target genes were idenitifed as differentially expressed when compared to control embryos. Expression studies have validated novel Dpp target genes and the list of genes that are regulated by BMP signalling has now been expanded. It can be invoked that these genes are involved in specification and/or mainentance of the amnioserosa tissue. Furthermore, I have uncovered a putative multi-tiered mechanism that exists between the Dpp and EGF signalling pathways to thus ensure correct cell fate specification and fine tuning of the Dpp signal in the Drosophila embryo. To further investigate how BMP signalling mediates such transcriptional regulation, a genome-wide RNAi screen was designed and performed to identify novel regulators of BMP transcription. Analysis of the screen data has identified a putative link between BMP-regulated transcription and transcriptional effectors of the Hippo signalling pathway, Scalloped and Yorkie. The data presented here suggests a co-regulatory requirement of these transcription factors to mediate Smad-dependent transcription.
42
Bücker, Sandra [Verfasser]. "BMP und SMAD Signale im kardiovaskulären System / Sandra Bücker." Gießen : Universitätsbibliothek, 2012. http://d-nb.info/1063954703/34.
43
Ribeiro, Alessandro Mendes. "BMP\'s em drenagem urbana - aplicabilidade em cidades brasileiras." Universidade de São Paulo, 2014. http://www.teses.usp.br/teses/disponiveis/3/3147/tde-24042015-115321/.
Abstract:
A ocupação desordenada e o grande percentual de superfície impermeabilizada em áreas urbanas, agravando os eventos extremos, é um dos problemas mais discutidos no meio técnico nacional e internacional. O conceito utilizado para projeto de drenagem urbana convencional, desta forma, tornou-se um tanto obsoleto nos dias de hoje, pois além dos problemas relativos aos picos elevados das tormentas, culminando em enchentes, principalmente nos grandes centros urbanos, há que se observar os aspectos de qualidade das águas pluviais. Neste sentido, começou-se a desenvolver na década de 1980 o conceito dos chamados BMP, do inglês, Best Management Practices, que consiste em técnicas que visam não somente o abatimento dos picos de eventos extremos como também a melhoria na qualidade da água precipitada com um enfoque mais ambiental. Procurou-se apresentar, ao longo do trabalho, o estágio de desenvolvimento dessas técnicas em vários países e a equalização das diversas terminologias utilizadas com o intuito de tornar estas ferramentas mais acessíveis ao meio técnico nacional, visando auxiliar no processo de mudança cultural brasileira. Analisou-se também a aplicabilidade dessas técnicas em um projeto real de drenagem urbana desenvolvido para a Prefeitura de São Paulo, na região do Butantã Zona Oeste, verificando-se a possibilidade de redução do sistema convencional ou sua eliminação com base nas informações técnicas elencadas.Unregulated occupation and the growing proportion of non-porous, covered urban surface area as aggravating factors in the effects of extreme weather events is one of the most talked about problems in national (Brazilian) and international technical circles. This factor has rendered the conventional methods historically applied when planning urban stormwater drainage somewhat obsolete because, in addition to the flash floods caused by intense downpours and storms in large metropolitan centers, the quality of the stormwater itself is deteriorating. To combat these effects, the initial foundations of the BMP (Best Management Practices) were laid down in the 1980\'s to develop methods to not only diminish the effects of extreme events but also to improve the quality of the water deposited by focusing on environmentally friendly urban planning. In this study, an attempt has been made to illustrate the developmental stage of these methods in several countries and to standardized the different technical terms used so that such tools become more accessible to the relevant Brazilian technical field and thereby further the respective process of cultural change in Brazil. It has also been analyzed how these methods could be applied to an actual urban drainage plan developed for the São Paulo City Hall implemented in the Butantã district in the city\'s \'Western Zone\' by assessing the possibility of reducing the conventional system or even eliminating it, based on the technical information studied.
44
Herhaus, Lina. "The regulation of TGFβ/BMP signalling by deubiquitylating enzymes." Thesis, University of Dundee, 2014. https://discovery.dundee.ac.uk/en/studentTheses/c53aed5a-920b-4290-a82c-f30b7d807ec6.
Abstract:
The transforming growth factor-ß (TGFß) pathway, including the bone morphogenetic protein (BMP), plays critical roles during embryogenesis and in adult tissue homeostasis. Hence, malfunctions in TGFß/BMP signalling result in several diseases. Signalling is initiated by ligand binding to cell surface receptor kinases, which phosphorylate and activate the R-SMAD transcription factors. R-SMADs translocate to the nucleus and regulate the transcription of hundreds of genes. The cellular responses to TGFß/BMP signals are tightly controlled and highly regulated. TGFß/BMP receptors and R-SMADs, as the intracellular mediators of TGFß/BMP ligands, are key targets for regulation to control duration and potency of signalling. Reversible ubiquitylation of R-SMADs and TGFß/BMP receptors is a key mechanism to control TGFß/BMP signalling. Several E3 ubiquitin ligases have been reported to regulate the turnover and activity of TGFß/BMP receptors and R-SMADs, however little is known about their cognate deubiquitylating enzymes (DUBs). A proteomic screen identified the DUBs OTUB1 and USP15 as potential novel regulators of the TGFß and BMP pathways respectively. Endogenous OTUB1 was recruited to the active phospho-SMAD2/3 complex only upon TGFß induction and OTUB1 had a crucial role in TGFß-mediated gene transcription and cellular migration. OTUB1 inhibited the ubiquitylation of phospho-SMAD2/3 by binding to and inhibiting the E2 ubiquitin-conjugating enzymes independently of its catalytic activity. Consequently, the depletion of OTUB1 in cells caused a rapid loss in levels of TGFß-induced phospho-SMAD2/3, which was rescued by the proteasomal inhibitor Bortezomib. These findings demonstrated a novel signal-induced phosphorylation-dependent recruitment of OTUB1 to its target. Hence, OTUB1 could be exploited as a target to intervene against diseases that are provoked by an imbalance in TGFß signalling. DUBs are highly regulated enzymes and recent reports have shed light into the molecular regulation OTUB1. The N-terminal region of OTUB1 harbours an ubiquitin binding domain, which is critical for its function to inhibit ubiquitylation. While investigating the role of OTUB1 in TGFß signalling, it became apparent that OTUB1 itself could be post-translationally modified by phosphorylation. Two phosphorylation sites at the OTUB1 N-terminal region have been identified by mass spectrometry. S18 of OTUB1 was phosphorylated in vitro by the type I TGFß receptor (ALK5), whereas S16 was phosphorylated by the constitutively active kinase CK2 in vitro and in vivo. Phosphorylation of the OTUB1 N-terminal region could affect its physiological function and requires further investigation. Although much is known about DUBs that target the type I TGFß receptor, no DUBs that target the type I BMP receptors had been identified. USP15 was identified in a proteomic screen as an interactor of SMAD6, which is a negative regulator of the BMP pathway. USP15 also binds to and deubiquitylates the type I BMP receptor (ALK3), thereby enhancing BMP signalling. Consequently, USP15 impacts BMP-induced SMAD1 phosphorylation, mouse osteoblastic differentiation and Xenopus embryogenesis. A proteomic approach identified O-GlcNAc transferase (OGT) as an interactor of SMAD2. SMADs have not been associated with O-GlcNAc modifications and the regulation of TGFß/BMP signalling by O-GlcNAcylation has not been investigated. Endogenous SMADs1-3 bound OGT and pulled down potential O-GlcNAc modified proteins. Furthermore, SMAD4 was possibly O-GlcNAcylated, which implies that O-GlcNAc modification could regulate TGFß/BMP signalling. Further investigation is needed to decipher the precise molecular mechanisms of this potential regulation.
45
Hodges, Clayton Christopher. "Optimization of BMP Selection for Distributed Stormwater Treatment Networks." Diss., Virginia Tech, 2016. http://hdl.handle.net/10919/81698.
Abstract:
Current site scale stormwater management designs typically include multiple distributed stormwater best management practices (BMPs), necessary to meet regulatory objectives for nutrient removal and groundwater recharge. Selection of the appropriate BMPs for a particular site requires consideration of contributing drainage area characteristics, such as soil type, area, and land cover. Other physical constraints such as karst topography, areas of highly concentrated pollutant runoff, etc. as well as economics, such as installation and operation and maintenance cost must be considered. Due to these multiple competing selection criteria and regulatory requirements, selection of optimal configurations of BMPs by manual iteration using conventional design tools is not tenable, and the resulting sub-optimal solutions are often biased. This dissertation addresses the need for an objective BMP selection optimization tool through definition of an objective function, selection of an optimization algorithm based on defined selection criteria, development of cost functions related to installation cost and operation and maintenance cost, and ultimately creation and evaluation of a new software tool that enables multi-objective user weighted selection of optimal BMP configurations.
A software tool is developed using the nutrient and pollutant removal logic found in the Virginia Runoff Reduction Method (VRRM) spreadsheets. The resulting tool is tested by a group of stormwater professionals from the Commonwealth of Virginia for two case studies. Responses from case study participants indicate that use of the tool has a significant impact on the current engineering design process for selection of stormwater BMPs. They further indicate that resulting selection of stormwater BMPs through use of the optimization tool is more objective than conventional methods of design, and allows designers to spend more time evaluating solutions, rather than attempting to meet regulatory objectives.Ph. D.
46
Schirwis, Elija. "Skeletal muscle growth and maintenance depend on BMP signaling." Thesis, Paris 6, 2014. http://www.theses.fr/2014PA066057.
Abstract:
Les facteurs de croissance de la superfamille TGF-β jouent un rôle dans toutes les étapes de la myogenèse prénatale et régissent l'entretien des muscles adultes. Les protéines morphogénétiques osseuses (BMPs) sont membres de la sous-famille des TGF-β et sont à l’origine de signaux clés régulant le développement musculaire embryonnaire. Cette thèse étudie le rôle de la signalisation BMP dans les cellules souches musculaires, dénommées cellules satellites. J'ai montré qu’après la naissance les BMPs régulent la croissance des fibres musculaires dépendante des cellules satellites. Suite à l’inhibition de la voie BMP, j'ai observé que les précurseurs myogéniques deviennent quiescents et cessent de progresser vers la différenciation, tandis que le traitement avec BMP4 suffit pour réactiver leur programme myogénique. La signalisation BMP affecte aussi la taille du muscle indépendante des cellules satellites. J'ai observé que les BMPs fournissent un signal hypertrophique et protègent de l’atrophie musculaire suite à une dénervation. Dans les conditions précédentes, la voie BMP inhibe l'expression de l’ubiquitine ligase E3, Fbxo30. J'ai analysé l'interaction entre la myostatine et la signalisation BMP. La myostatine est un autre membre de la famille des TGF-β, mais elle se lie à des récepteurs différents de ceux des BMPs. En l'absence de myostatine, l’hypertrophie musculaire dépend entièrement de la signalisation BMP. La dénervation musculaire chez les souris déficientes en myostatine provoque une atrophie, aggravée par l’inhibition des BMPs. Par conséquent, la voie BMP est un signal hypertrophique essentiel dans le muscle adulte qui prédomine sur la signalisation de la myostatineGrowth factors of the TGF-β superfamily play a role in all stages of prenatal myogenesis and govern adult muscle maintenance. Bone morphogenetic proteins (BMPs) are members of the TGF-β subfamily and are key signals that regulate embryonic and fetal muscle development. This work investigates the role of BMP signaling in muscle stem cells of the postnatal muscle, the satellite cells. I showed that BMPs regulate satellite cell-dependent growth of postnatal fibers and the generation of the satellite cell pool. After inhibition of BMP signaling, I observed that myogenic precursor cells become quiescent and fail to progress towards differentiation, whereas treatment with BMP4 on its own is sufficient to reactivate the myogenic program. BMP signaling also affects the size of the muscle in a satellite cell-independent manner. I found that BMPs provide a hypertrophic signal and protect from denervation-induced muscle atrophy. Under such condition, BMP signaling inhibits the expression of the E3 ubiquitin ligase Fbxo30. I further analyzed the interaction between myostatin and BMP signaling. Myostatin is another member of TGF-β superfamily, but myostatin and BMPs bind to different receptors for signaling. Large muscles in absence of myostatin entirely depend on the presence of BMP signaling. Denervation of muscle in myostatin mutant mice causes a strong muscle atrophy, which is aggravated by the inhibition of BMP signaling. Therefore, the BMP pathway is a fundamental hypertrophic signal in adult muscle and is dominant over myostatin signaling
47
Wang, Baigang. "BMP-Signale bei der Somitenentwicklung experimentelle Untersuchungen beim Vogelembryo /." [S.l. : s.n.], 2007. http://nbn-resolving.de/urn:nbn:de:bsz:25-opus-46970.
48
Capuccini, Enrico. "Applicazioni di tecnologie BMP ai sistemi di drenaggio urbano." Master's thesis, Alma Mater Studiorum - Università di Bologna, 2011. http://amslaurea.unibo.it/2032/.
49
Mohedas, Agustin Humberto. "Development of BMP type I receptor kinase inhibitors for the treatment of fibrodysplasia ossificans progressiva and the study of the BMP signaling pathway." Thesis, Massachusetts Institute of Technology, 2014. http://hdl.handle.net/1721.1/90173.
Abstract:
Thesis: Ph. D., Harvard-MIT Program in Health Sciences and Technology, 2014.164
Page 130 blank. Cataloged from PDF version of thesis.
Includes bibliographical references (pages 121-129).
The BMP signaling pathway is essential for embryonic development and the maintenance of tissue homeostasis. Dysregulated BMP signaling, both loss and gain-of-function, has been demonstrated in the pathogenesis of diseases including cancer, atherosclerosis, anemia and particularly hereditary disorders such as pulmonary arterial hypertension, hereditary hemorrhagic telangiectasia, and fibrodysplasia ossificans progressiva (FOP). FOP is a rare and disabling condition caused by a highly recurrent mutation in the ACVR1 gene encoding the BMP type I receptor activin-like kinase 2 (ALK2), characterized by the progressive heterotopic ossification (HO) of skeletal muscle and connective tissue leading to widespread joint immobilization, with significant morbidity and premature mortality. There are currently no effective treatments for FOP. The goal of this thesis is to develop and characterize highly selective BMP type I receptor inhibitors targeting ALK2 for the treatment of FOP. Despite the high degree of structural homology between all the BMP and TGF-[beta] type I receptors, I hypothesized that potent and selective inhibitors targeting a single BMP type I receptor, ALK2, could be developed based on a previously identified pyrazolo[1,5-a]pyrimidine core scaffold. I screened a library of pyrazolo[1,5-a]pyrimidine derivatives in a high throughout sensitive radiometric assay of BMP and TGF-[beta] type I receptor kinase activities. I identified a derivative with a unique chemical moiety (5-quinoline) that demonstrated high selectivity for ALK2, but with lower potency than the parent molecule. We synthesized a new 5-quinoline derivative with increased potency and selectivity for ALK2 over the other BMP type I receptors and greatly improved selectivity against the TGF--[beta] type I receptors. I used this highly selective compound to examine ALK2-mediated BMP signaling in vitro and demonstrated in vivo efficacy in two mouse models of HO. In a complementary approach, we generated a library of novel BMP type I receptor inhibitors based on the 2-aminopyridine core scaffold. I developed a structure activity relationship to determine the key structural elements responsible for potency and selectivity. We identified a several novel derivative compounds with improved potency and selectivity for ALK2 over the parent. We successfully used this set of derivatives to address a specific question in FOP biology, of whether ATP-competitive kinase inhibitors exert differential activity against wild-type or diverse FOP-causing ALK2 mutants. Finally, in our SAR of pyrazolopyrimidine compounds, we identified a highly potent inhibitor of both BMP and TGF-[beta] type I receptor activity. I characterized the ability of this compound to inhibit ligand-induced BMP and TGF-[beta] signaling in a variety of cell culture models, as well as inhibit the activity of individual type I receptors. We then used this compound to examine the contribution of individual BMP and TGF-[beta] receptors to signal transduction. We used the broad activity of this inhibitor to limit signaling of all endogenous BMP and TGF-[beta] type I receptors in cells, while reconstituting the activity of specific type I receptors using engineered, inhibitor-resistant mutant receptor kinases which we developed by modifying gatekeeper residues critical for interactions with inhibitor. These mutant receptor kinases demonstrated preserved basal and ligand-mediated signaling functions which were unaffected by inhibitor. These results demonstrate proof-of-principle of a system for examining the function of individual receptors of this pathway in isolation. The work presented in this thesis advances the development of novel BMP type I receptor kinase inhibitors of high selectivity and potency which could serve as important tools for the study of BMP signaling and as therapies for diseases of excessive BMP signaling such as FOP. Development of highly potent and selective inhibitors of ALK2 offers the hope of rational disease modifying therapy for the treatment of FOP.
by Agustin Humberto Mohedas.
Ph. D.
50
Drevelle, Olivier. "Influence d'un film de polycaprolactone fonctionnalisé par des peptides d'adhésion sur la réponse de préostéoblastes à la BMP-2 et à la BMP-9." Thèse, Université de Sherbrooke, 2013. http://hdl.handle.net/11143/6122.
Abstract:
L'efficacité des matériaux utilisés pour favoriser la régénération osseuse dépend entre autres de leur capacité d'interaction avec le tissu environnant. Ainsi, des peptides d'adhésion contenant la séquence Arginine-Glycine-Acide aspartique (RGD) sont parmi les plus utilisés pour favoriser 1'attachement des cellules osseuses au matériau. Les facteurs de croissance, dont les protéines morphogénétiques osseuses (BMPs), jouent également un rôle clé dans le processus de différenciation et de fonctionnement des cellules osseuses. La BMP-2 approuvée par la Food and Drug Administration aux États-Unis dans le cadre d'un système de libération est déjà actuellement utilisée cliniquement pour accroître la régénération osseuse. De plus, la BMP-9 a récemment suscité un grand intérêt en raison de son potentiel ostéogénique supérieur à celui de la BMP-2. Néanmoins, peu d'études se sont intéressées à l'influence des peptides d'adhésion sur la réponse cellulaire aux BMPs. Le principal objectif de ce travail de doctorat a donc été de fonctionnaliser un polymère par des peptides d'adhésion et de déterminer son impact sur la capacité de préostéoblastes de souris MC3T3-E1 à répondre à la BMP-2 et à la BMP-9. Cette étude s'est tout d'abord intéressée à la synthèse et à la caractérisàtion d'un film de polycaprolactone (PCL) fonctionnalisé par un peptide dérivé de la sialoprotéine osseuse qui contient 15 acides aminés dont la séquence RGD (pRGD). La fonctionnalisation a consisté en une hydrolyse alcaline du film PCL suivie d'un greffage covalent du pRGD. Les films PCL hydrolysés ont adsorbé des protéines sériques adhésives fibronectine et vitronectine mais sans favoriser l'étalement des préostéoblastes MC3T3-E1. En absence de sérum, les films PCL-pRGD ont permis un étalement plus important des préostéoblastes MC3T3-E1 par rapport au PCL fonctionnalisé par le pRGE (peptide négatif) ou au PCL hydrolysé. Le PCL-pRGD a augmenté le niveau de phosphorylation de la FAK (Tyr 397 ), évènement nécessaire chez les préostéoblastes murins pour permettre leur différenciation en ostéoblastes matures. Ainsi, seules les cellules adhérant au PCL-pRGD ont répondu à la BMP-2 via une activation de la voie canonique des Smads. Dans un deuxième temps, la stimulation des préostéoblastes par la BMP-2 et/ou BMP-9 a été déterminée sur PCL-pRGD. L'EC50 pour chacune des BMPs a tout d'abord été évaluée afin de choisir la concentration optimale à utiliser lors de la combinaison des BMP-2/BMP-9. Tandis que la BMP-2 a induit une phosphorylation des Smad1/5/8 dès 30 min, la BMP-9 a engendré un retard d'activation à 4 h. Cette observation était concomitante avec une diminution de la ?-caténine. Par contre, aucune différence n'a été observée avec la BMP-2 et la BMP-9 en termes d'activation des MAPKinases. Néanmoins, tant la BMP-2 que la BMP-9 ont été capables d'induire la différenciation des préostéoblastes MC3T3-E1 sur PCL-pRGD telle que mis en évidence par la synthèse d' ARNm codant pour Dlx5, Ostérix ou l'ostéocalcine et l'augmentation de l'activité de l'alcaline phosphatase à 72h. Mais l'utilisation d'une combinaison de la BMP-2 avec la BMP-9 stabilisant la ?-caténine n'a pas permis d'obtenir un effet additif sur la différenciation, des activations semblables à celles de la BMP-2 utilisée seule ayant été alors observées. En résumé, l'utilisation de BMP-2 ou de BMP-9 en combinaison avec une surface fonctionnalisée par des peptides d'adhésion semble être une voie prometteuse pour favoriser la différenciation cellulaire. Cependant, cette étude montre également que la BMP-2 et la BMP-9 induisent des voies d'activation antagonistes au contact du PCL-pRGD. Elle met donc l'emphase sur la nécessité de mieux comprendre l'influence de la fonctionnalisation de matériaux par des peptides d'adhésion sur la réponse aux facteurs de croissance.