Дисертації: "FKBPs"

1

Fabian, Anne-Katrin [Verfasser], and Christoph [Akademischer Betreuer] Turck. "InterAKTion with FKBPs : modulation of the Akt/mTOR pathway by FKBPs / Anne-Katrin Fabian ; Betreuer: Christoph Turck." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2013. http://d-nb.info/1132061113/34.

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2

Xiol, Jordi. "Etudes fonctionnelles sur les composants de la voie des piRNAs MOV10L1 et FKBP6." Phd thesis, Université de Grenoble, 2011. http://tel.archives-ouvertes.fr/tel-00664995.

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Les piwi-interacting RNAs (piRNA) interagissent avec les protéines qui font partie de la branche PIWI de la famille des Argonautes. Ils participent à la répression des transposons dans la ligne germinale. Chez la souris, les protéines PIWI sont indispensables pour la fertilité des mâles et sont responsables de la méthylation de l'ADN au niveau des promoteurs des transposons. Les piRNA sont produis à partir de deux mécanismes: la biogenèse primaire et le cycle d'amplification ping-pong. Nous avons fait des études fonctionnelles sur deux protéines qui participent à la voie des piRNA: l'hélicase d'ARN MOV10L1 et l'immunophiline FKBP6. Nous avons décrit le rôle de MOV10L1 en tant que facteur de biogenèse primaire. La disruption génétique du domaine hélicase de MOV10L mène à une activation des transposons et à une perte de la méthylation de l'ADN. Ainsi, les piRNA ne sont pas produits chez le mutant, ce qui suggère que MOV10L1 est essentielle pour la biogenèse des piRNA. Tdrd1 interagit avec les protéines PIWI et joue un rôle dans la voie des piRNA en recrutant quelques facteurs à partir de son domaine MYND N-terminal. Nous avons montré que le domaine MYND de Tdrd1 interagit avec FKBP6, une protéine qui appartient à une famille d'isomérases de prolines qui sont présentes dans des complexes de chaperonnes. Les études biochimiques réalisées indiquent que FKBP6 est inactive et qu'elle utilise son domaine isomérase comme un module structural qui interagit avec les protéines PIWI, alors qu'elle interagit avec Hsp90 avec son domaine TPR. L'analyse d'une souris mutante pour fkbp6 a révélé une dérépression des transposons et une perte de la méthylation de l'ADN, mais peu d'effets sur la biogenèse primaire. Ces résultats sont en accord avec un rôle de FKBP6 en aval de Tdrd1, et nous pouvons penser que ce rôle pourrait être le recrutement de Hsp90 pour participer au cycle d'amplification ping-pong.

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3

Garrido, Marine. "Identification de la protéine chaperonne FKBP7 comme une nouvelle cible thérapeutique dans le cancer de la prostate résistant à la chimiothérapie." Thesis, Université Paris-Saclay (ComUE), 2016. http://www.theses.fr/2016SACLS181/document.

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Le cancer de la prostate est le second cancer diagnostiqué chez les hommes dans le monde. Malgré le développement de nouveaux traitements au cours de ces cinq dernières années, les chimiothérapies par taxanes, docetaxel et cabazitaxel, restent des traitements de référence dans la prise en charge des patients atteints de cancer de la prostate métastatique résistant à la castration. Cependant, des résistances primaires et acquises émergent chez environ la moitié des patients. C’est pourquoi, il est urgent de découvrir et de comprendre les mécanismes de résistance aux taxanes afin d’identifier de nouvelles cibles thérapeutiques. En effet, de nouvelles thérapies ciblées peuvent émerger de la compréhension des voies de signalisation impliquées dans le cancer de la prostate pour contourner la chimiorésistance et améliorer les traitements. Les protéines chaperonnes jouent un rôle clef dans la régulation de l’homéostasie cellulaire et dans le développement de résistance aux traitements. Elles constituent donc des cibles thérapeutiques potentielles pour contourner la chimiorésistance. En réalisant un criblage fonctionnel par siARN à partir de profils d’expression génique, nous avons identifié FKBP7, une chaperonne moléculaire encore jamais étudiée chez l’homme, impliquée dans la résistance au docetaxel et au cabazitaxel. FKBP7 est surexprimée dans les tumeurs de la prostate et son expression est corrélée avec la récurrence chez les patients ayant reçu du docetaxel en thérapie néoadjuvante. De plus, FKBP7 est surexprimée dans des lignées cancéreuses prostatiques résistantes aux taxanes et son expression est nécessaire à leur croissance in vitro et à la croissance tumorale dans un modèle murin de résistance au docetaxel. Par des approches de protéomique haut-débit, nous avons identifié la voie de signalisation régulée par FKBP7 qui est responsable de la survie des cellules chimiorésistantes. Enfin, nous proposons une stratégie thérapeutique pour contourner la chimiorésistance au docetaxel et au cabazitaxel en ciblant l’effecteur moléculaire en aval de FKBP7
Prostate cancer is the second cancer diagnosed among men worldwide. Beside approval of new therapies in the last five years, chemotherapeutic agents, docetaxel and cabazitaxel taxanes remain key treatments for metastatic castration resistant prostate cancers. However, primary and acquired resistance to taxanes still emerged in about half of patients. There is therefore an urgent need to discover and understand the taxane resistance mechanisms in order to identify new therapeutic targets. Indeed, targeted therapies that exploit the signaling pathways involved in prostate cancer are required to overcome chemoresistance and improve treatment outcomes. Molecular chaperones play a key role in the regulation of cellular homeostasis and the development of treatment resistance, and are promising therapeutic targets. Using high throughput siRNA functional screening based on a gene expression signature, we identified FKBP7, involved in acquired resistance to docetaxel and cabazitaxel. FKBP7 is a molecular chaperone that has not been studied in human so far. FKBP7 is overexpressed in prostate tumors and its expression is correlated with recurrence in patients who received docetaxel as neoadjuvant therapy. Moreover, FKBP7 is upregulated in taxane resistant prostate cancer cell lines and its expression sustains their growth in vitro and in a mice model of Docetaxel resistance. Using a high throughput proteomic approach, we identified the signaling pathway regulated by FKBP7 which is responsible for the survival of chemoresistant cells. Finally, we proposed a promising therapeutic strategy to overcome both docetaxel and cabazitaxel chemoresistance by targeting the downstream effector of FKBP7

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4

Blair, Laura J. "Age-associated increases in FKBP51 facilitate tau neurotoxicity." Scholar Commons, 2014. https://scholarcommons.usf.edu/etd/5185.

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Tau is a protein which regulates microtubule stability and is heavily involved in axonal transport. This stability is dynamically controlled in part by over 40 phosphorylation sites across the tau protein which allows for binding and release from the microtubules. However, if abnormal hyperphosphorylation occurs, tau dissociates from the microtubules. Once released, the microtubules become unstable and the aberrant tau mislocalizes from the axon to the somatodendric compartment, where it aggregates. These aggregates are made of many pathological forms of tau including oligomeric species, paired helical filaments, and neurofibrillary tangles, all of which have associated toxicities. Tau pathology is a hallmark of Alzheimer's disease, one of over 15 diseases known as tauopathies which present with tau pathology, all of which lack effective treatments. Heat shock protein 90 kDa (Hsp90) is a major adenosine triphosphate (ATP)-dependent regulator of non-native proteins, like misfolded tau. Although Hsp90 is able to effectively refold and degrade many aberrant proteins, it has been associated with preserving aberrant tau. In fact, inhibiting the Hsp90 ATPase activity leads to the degradation of tau, which has been demonstrated in a number of models with the use of various Hsp90 inhibitors. However, there are many side-effects associated with the use of these inhibitors including toxicity and heat shock factor 1 (HSF1) activation. Although improvements on Hsp90 inhibitors are still in progress, this study explores targeting Hsp90 through a slightly different mechanism, by targeting Hsp90 co-chaperones. Hsp90 is involved in almost every pathway in each cell throughout the body. Co-chaperone proteins assist Hsp90 in these various processes, but are each only involved in a subset of the total Hsp90 interactome. Therefore, targeting Hsp90 co-chaperones could lead to improved efficacy, potency, and safety of drugs designed toward Hsp90 for the treatment of tauopathies. We previously showed one of these co-chaperones, FK506 binding protein 51 kDa (FKBP51), a tetratricopeptide repeat (TPR) domain containing immunophilin, coordinates with Hsp90 to regulate tau metabolism. More specifically, we found that increases and decreases in FKBP51 levels correlated with increases and decreases in tau levels, respectively. FKBP51 knockout mice have been extensively studied and have shown no negative phenotypes in these characterizations. In this study, we found that this mouse model has decreased endogenous tau levels. Furthermore, this study demonstrates that FKPB51 colocalizes with pathological tau in the AD brain, and synergizes with Hsp90 to preserve tau from proteasomal degradation. Additionally, FKBP51 overexpression in mouse model of tau pathology leads to the preservation of tau. We went on to characterize this accumulated tau as being neurotoxic and oligomeric in nature, while being low in silver positive, β-sheet structure. In the human brain, we found that FKBP51 is strikingly increased with aging and even further in the AD brain. In support of these findings, we also found age-associated decreased methylation in the FKBP5 gene, which encodes FKBP51. Moreover, we found that increasing levels of FKBP51 caused other co-chaperone to have reduced Hsp90 binding and led to tau preservation. This supports a model where age-related increases in FKBP51 lead to the preservation of misfolded tau species and ultimately disease. In order to model the high FKBP51 expression found in the aging brain, we generated the first FKBP5 overexpressing mouse model, which is tet-regulatable. This mouse, rTgFKBP5, was made by targeted, single insertion of the human FKBP5 gene into the HIP11 locus of the mouse genome crossed with CamKIIα tTa mice. We have now confirmed high FKBP51 levels in the forebrain and hippocampus of this mouse, which will serve as a testing platform for FKBP51 regulating drugs. Overall, this work exemplifies FKBP51 as an important regulator of tau metabolism through Hsp90. With the absence of a negative phenotype in mice ablated of FKBP51 and the development of this novel, FKBP51 overexpressing mouse model, strategies designed to decrease FKPB51 levels or to disrupt the FKBP51/Hsp90 complex could be relevant for the treatment of tauopathies, like AD.

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5

Annett, Stephanie Louise. "The role of FKBPL and its peptide derivatives in targeting stemness." Thesis, Queen's University Belfast, 2017. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.725332.

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FKBPL is a secreted protein with well-established anti-angiogenic activity and a novel therapeutic peptide, ALM201, derived from the protein has entered Phase l/ll clinical trial in ovarian cancer patients. Ovarian cancer is the most lethal gynaecologic cancer with a high incidence of recurrent chemo-resistant disease and this has been attributed to a subpopulation of cancer stem cells (CSCs), which escape standard therapies and drive metastatic spread. ALM201 binds to the cell surface receptor antigen, CD44, a classic marker of CSCs, and for the first time, we demonstrate ALM201's ability to target ovarian CSCs. Tumoursphere assays have demonstrated that ALM201 is effective at reducing ovarian CSCs in a range of cell lines and primary patient samples in vitro and reduced the CD44+CD117+ ovarian CSC subpopulation. Clonogenic assays suggest that ALM201 mediates ovarian CSC differentiation; a similar observation was previously noted in breast cancer. In vitro ALM201 displayed potent anti-CSC activity in the high grade serous (HGS) ovarian cancer cell line, OVCAR3, however, it displayed no anti-angiogenic or anti-CSC efficacy in in vivo models. In contrast, ALM201 treatment of Kuramochi xenografts resulted in significant growth delay and a 10 fold decrease in CSCs in in vivo experiments. Upon CD31/PAS staining, the Kuramochi xenografts displayed an extensive CD31+ vasculature network, which was disrupted by treatment with ALM201. On the other hand, the OVCAR3 xenografts had relatively few CD31+ blood vessels but had extensive PAS+ vasculogenic mimicry (VM) networks; which ALM201 did not target. Furthermore, OVCAR3 xenografts dramatically up regulated the inflammatory cytokines IL-6 and IL-8, in comparison to the Kuramochi xenografts, and as a result ALM201 had no effect on the CSC sub-population. In a tissue microarray of HGS ovarian cancer patients, high FKBPL expression correlated with an increase in progression free interval thus indicating a role for FKBPL as a prognostic biomarker in the clinic. Endocrine therapies are commonly used to prevent ER+ breast cancer release however, findings suggest that they may be increasing treatment resistant breast CSCs. FKBPLs preclinical peptide AD-01 has previously shown potent anti-CSC activity in the breast cancer setting and here we demonstrate its ability to abrogate endocrine enrichment of CSCs in both cell lines and patient samples. Furthermore, we demonstrate using in vivo limiting dilution models that ALM201 alone or in combination with tamoxifen was effective at delaying tumour recurrence by 12 days and 21 days, respectively. FKBPL and its peptide derivatives down regulate the DLL4/Notch pathway, a regulator of CSC self-renewal, thus indicating a novel mechanism of action. In the haemopoietic setting, ALM201 inhibited migration of chronic lymphocytic leukaemia (CLL) - like cell lines without inducing apoptosis. In an in vivo model of CLL, treatment of ALM201 resulted in a compartmental shift of the cells from the bone marrow to the peripheral blood and spleen. Furthermore, in vitro studies of acute lymphocytic leukaemia (AML) cell lines show that the combination of ALM201 and all trans retinoic acid (ATRA) significantly reduces cell viability, compared to ATRA alone. Analysis of AML cell morphology indicates that ALM201 may be inducing cellular differentiation and thus overcoming the characteristic maturation arrest of this disease. In summary, high FKBPL levels is associated with progression free survival in HGS ovarian cancer patients and the clinical FKBPL peptide, ALM201, effectively targets angiogenesis and CSCs in well-vascularised HGS ovarian cancer thus enhancing the efficacy of this agent in the clinic. In addition, we have demonstrated additional indications for ALM201 in treating endocrine resistance in breast cancer and a novel role in haematopoietic malignancies.

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6

Patel, Satyam Gunvantbhai. "Characterization of amygdalar Fkbp5 role in stress-induced anxiety-like behaviour." Thesis, University of Leicester, 2012. http://hdl.handle.net/2381/27663.

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The physiological response to excessively strong aversive stimuli – the stress response – is relatively maladaptive and leads to various psychopathologies such as anxiety disorders only in a minority of individuals. Our lab has previously shown that severe acute restraint stress heightens anxiety-like behaviour in wild-type but not in the extracellular serine protease, neuropsin, deficient mice. Dissecting molecular changes underlying genotypic differences, our microarray and qRT-PCR approaches revealed that the stress-induced upregulation of glucocorticoid receptor (GR) co-chaperone, Fkbp5, expression in the amygdala is significantly attenuated in neuropsin-/- mice compared to the wild-type mice and attenuated expression can be restored by bilateral intraamygdala injection of recombinant neuropsin. Further, blocking neuropsin cleavage of EphB2 with anti-EphB2 antibody suppressed only neuropsin-mediated but not corticosterone-driven upregulation of Fkbp5 expression in primary amygdala cultures unraveling novel neuropsin-dependent mechanism acting in synergy with the well characterized corticosterone pathway to mediate the robust stress-effect on Fkbp5 expression. Importantly, wild-type mice lacking amygdala specific Fkbp5 exhibit stress protective phenotype in unconditioned anxiety tests. Therefore, this study characterizes and concludes an indispensable role of amygdalar Fkbp5 in stressful episodes developing into anxiety disorders.

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7

Wiechmann, Tobias [Verfasser], and Mathias [Akademischer Betreuer] Schmidt. "Epigenetic mechanisms of fine-tuning FKBP5 gene expression / Tobias Wiechmann ; Betreuer: Mathias Schmidt." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2019. http://d-nb.info/1222436531/34.

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8

Acino, Erin Reese. "Transcriptional Regulation of the Mouse FKBP5 Gene by Progesterone and Glucocorticoid Receptor Binding." Thesis, The University of Arizona, 2010. http://hdl.handle.net/10150/146207.

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Steroid hormone receptors bind to DNA and interact with transcription-regulating proteins to affect a change in gene expression levels. However, questions remain about their choice of binding sites in vivo and their cooperation with other transcription factors. This experiment uses chromatin immuno-precipitation (ChIP) to attempt to identify progesterone and glucocorticoid receptor binding sites in the mouse FKBP5 gene. However, no sites were identified due to poor-quality sheared chromatin. Use of a circulating water bath to maintain low temperatures during sonication could improve consistency in future experiments, and more cellular material could increase the likelihood of successful immuno-precipitations.

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9

Neumann, Jacob Trevor. "THE ROLE OF ATP AND FK-506 BINDING PROTEIN IN THE COUPLED GATING OF SKELETAL RYANODINE RECEPTORS." OpenSIUC, 2011. https://opensiuc.lib.siu.edu/dissertations/348.

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During skeletal muscle stimulation, there is a summation of local events of Ca2+ release from the sarcoplasmic reticulum, known as Ca2+ sparks. Ca2+ sparks originate from groups of skeletal ryanodine receptors (RyR1) that activate and close in synchrony. This synchrony allows for the rapid and massive release of Ca2+ from the sarcoplasmic reticulum to initiate contraction and, more important, would provide a mechanism to terminate Ca2+ release under conditions where independent RyR1 are normally active. RyR1 mutations can result in abnormal intracellular Ca2+ signaling that is associated with numerous skeletal muscle disorders including malignant hyperthermia and central core disease. Therefore, investigating the mechanisms that control RyR1 function can help identify how these mutations cause deleterious Ca2+ handling. Currently, most published research on RyR1s gating utilizes single RyR1 reconstituted into planar lipid bilayers to test isolated RyR1. However, in vivo, arrays of RyR1 function in synchrony. Attempts to reconstitute RyR1s into planar lipid bilayers result in experiments that contain multiple channels, which under specific conditions may gate in synchrony, also known as coupled gating. Coupled RyR1 gating was first reported by A. Marks' laboratory and attributed to FK-506 binding protein 12 (FKBP12) associating with neighboring RyR1s the stabilization of RyR1-RyR1 interactions that promote coupled gating. Previous studies suggested that ATP is required for coupled RyR1 gating; however, the mechanism by which ATP promotes the coordinated activity of RyR1s has not been elucidated and is the focus of this thesis. Therefore, my hypothesis is that the agonist action of ATP and FKBP12 bound to RyR1 are required for coupled RyR1 gating. In addition, new pharmacological tools are required to better understand coupled RyR gating. Thus, an additional goal is to identify pharmacological agents that modulate RyR1s in an innovative manner, i.e., help to uncover novel aspects of RyR1 gating and conduction. This investigation suggests that the adenosine based nucleotides, ATP, ADP and AMP, are agonists of RyR1s and promote coupled RyR1 gating in planar lipid bilayers. However, ADP and AMP were unable to maintain coupled RyR1 gating with physiological levels of Mg2+. This suggests that coupled gating would be impaired when the levels ATP decrease, as in muscle fatigue. When ATP was compared to other nucleotides (GTP, ITP, and TTP), the results suggest that the nucleotide agonist action on RyR1s is dependent on the phosphate groups and amino group on the nucleobase. As ATP is the most efficient nucleotide for coupled gating, I also investigated the indirect action of ATP to act as a kinase substrate or alter the cytoskeletal network. The addition of kinases, phosphatases and cytoskeletal modulators did not produce a significant disruption of coupled RyR1 gating. I also tested the role of addition of exogenous FKBP12 to RyR1s that gated independently or had partial coupling, but coupled gating was never improved. Also, the addition of high doses of rapamycin to remove FKBP12 from coupled RyR1 failed to functionally uncouple the channels. Finally, I attempted to find pharmacological agents that could aid in the understanding of coupled RyR1. Some agents were found to modulate RyR1s; however, I did not find a probe that would affect kinetics/conductance of RyR1s and was suitable for comparing coupled gating in bilayers with Ca2+ sparks in cells. Overall, coupled RyR gating is dependent on the physiological modulators ATP and Mg2+. This thesis represents a step forward in identifying the requirements for coupled RyR1 gating and understanding how RyR1s function in cells. Until an understanding of how these receptors communicate in cells is obtained, how different mutations alter the Ca2+ leak will continue to be quite difficult to study.

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10

Donley, Christopher Blair. "The role of the oestrogen receptor interacting proteins, FKBPL and RBCK1, in breast cancer signalling." Thesis, Queen's University Belfast, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.601364.

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The aim of this thesis was to further characterise the role of FKBPL and RBCKl in the ERa: signalling pathway. Both RBCKl and FKBPL were found to interact with Hsp90 and ER and this interaction was enhanced by E2. Both RBCKl and FKBPL appear [0 be regulated by the oestrogen. However, both FKBPL and RBCKl bind along with ER« to the promoter of pS2, suggesting a potential role for FKBPL and RBCKl in ERa: trans-activation. RBCKl was shown [0 be the ubiquitin ligase for FKBPL. RBCKl was shown to facilitate the attachment of linear chains of ubiquitin to FKBPL. SiRNA knockdown of RBCKl resulted in increased levels of FKBPL in the T47D cell line, but inversely down-regulation of RBCKl in the MCF-7 cell line resulted in a reduction in FKBPL protein levels, suggesting that there is differential regulation of FKBPL by RBCKl depending on the cell line. FKBPL also appears to have a potential role in regulating the self-ubiquitination of RBCK1. RBCKl was also shown to regulate p21 transcription in a mechanism that was independent of p53. RBCKl siRNA knockdown resulted in increased p21 levels but overexpression of RBCKl in the MCF-7 cell line also increased p21 protein levels, suggesting that RBCKl regulates p21 levels through some post-translation modification, possibly through Akt. High levels of FKBPL and RBCKl were independently shown to correlate with increased patient survival in microarray data sets, and a combination of both high RBCKl and FKBPL was the most favourable phenotype. Finally the levels of RBCKl were shown to reduce the efficacy of tamoxifen in the MCF-7 and T47D cell lines, high RBCKl correlated with decreased tamoxifen efficacy. This effect was mirrored in a • micro-array data set, showing high RBCKl predicted worse response for tamoxifen therapy. Therefore RBCKl and FKBPL have potential as novel biomarkers for endocrine therapy.

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11

Byrne, C. "The Role of FKBPL in Steroid Hormone Receptor Signalling; Implications for Response to Endocrine Therapy." Thesis, Queen's University Belfast, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.517229.

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12

McClelland, K. "Characterisation of a Novel Protein FKBPL/DIR1; Implications for Pathways Controlling Cell Growth and Survival." Thesis, Queen's University Belfast, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.501322.

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13

McClements, Lana. "Targeting treatment resistant breast cancer stem cells with FKBPL and its peptide derivative, AD-01." Thesis, Queen's University Belfast, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.675459.

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FKBPL and its peptide derivative, AD-01, have already demonstrated well-established inhibitory effects on breast cancer growth and CD44 dependent anti-angiogenic activity. FKBPL stable overexpression or AD-O! treatment were highly effective at reducing the BCSC population measured by inhibiting mammosphere forming efficiency (MFE) in cell lines and primary breast cancer samples from both solid breast tumours and pleural effusions. Flow cytometry, to assess the ESA+/CD44+/CD24' subpopulation, validated these results. The ability of AD-01 to inhibit the selfrenewal capacity of BCSCs was confirmed across three generations of mammospheres, where mammospheres were completely eradicated by the third generation. Clonogenic assays suggested that AD-O! mediated BCSC differentiation, with a significant decrease in the number of holoclones and an associated increase in meroclones/paraclones. In support of this, the stem cell markers, Nanog, Oct4 and Sox2 were significantly reduced following AD-01 treatment, whilst transfection of FKBPL-targeted siRNAs led to an increase in these markers and in mammosphere forming potential, highlighting the endogenous role of FKBPL in BCSC signalling. The clinical relevance of this was confirmed using a publically available microarray data set (GSE7390), where high FKBPL and low Nanog expression were independently associated with improved overall survival in breast cancer patients. When AD-01 was combined with other agents, we observed additive activity with the Notch inhibitor, DAPT and AD-Ol was also able to abrogate a chemo- and radiotherapy induced enrichment in BCSCs. Importantly, using 'gold standard' in vivo limiting dilution assays we demonstrated a delay in tumour initiation and reoccurrence in AD-O! treated xenografts. The anti-BCSC mechanism of action of the FKBPL endogenous protein and its peptide derivative, AD-01, involves the CD44 and Notch pathway. In summary, AD-Ol appears to have dual anti-angiogenic and anti-BCSC activity which will be advantageous as this agent enters clinical trial.

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14

Bennett, Rachel. "Modulation of the anti-angiogenic protein FKBPL : implications for a host of diseases, including cancer." Thesis, Queen's University Belfast, 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.680888.

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FKBPL is a secreted anti-angiogenic protein, with a therapeutic peptide, ALM201, based on the active domain of FKBPL shortly entering phase I clinical trials. The aim of this thesis was to characterise the effects of FKBPL modulation on physiological and pathological angiogenesis, to identify FKBPL-associated pathways and to determine how FKBPL transcription, translation and secretion is mediated. To study the effects of FKBPL modulation on angiogenesis and tumour growth, a novel amphipathic peptide, RALA, was used to deliver FKBPL siRNA and FKBPL cDNA in vitro and in vivo, to ZR-75-1 xenografts; increased FKBPL was I associated with delayed tumour growth, prolonged survival and decreased microvessel density (MVD), whilst decreased I expression resulted in increased MVD and stemness. The physiological impact of endogenous FKBPL was established by development of a Fkbpl+/- mouse; Fkbpl-/- mice I were embryonically lethal prior to E8.5, suggesting a critical role for FKBPL in embryonic development. However, whilst Fkbpl+/- embryos showed some vascular irregularities, the mice developed normally. In murine angiogenesis models including the aortic ring, sponge, and tumour growth assays, Fkbpl+/- mice exhibited significantly increased sprouting, enhanced vessel recruitment and faster tumour growth, respectively, compared to their wild -type littermates, supporting the anti-angiogenic function of FKBPL. Furthermore, Fkbpl+/ mice were more prone to obesity and were less able to regulate glucose levels; interestingly, ALM201 was able to normalise this phenotype. SIRT1, a key gene involved in ; obesity and diabetes was positively regulated by FKBPL, both in vitro and in vivo, going some way to explaining these effects. Furthermore, manipulation of the SIRT pathway also potentiated the anti-tumour activity of FKBPL. The regulation of FKBPL by pro-angiogenic stimuli, and its secretory pathway was,also investigated. FKBPL was secreted via the Golgi body to a greater extent in human microvascular endothelial cells compared to tumour cells, in keeping with its anti-angiogenic role. Protein and mRNA expression was unaffected by hypoxia and other angiogenic cytokines, VEGF, bFGF or IL8; whilst hypoxia inhibited its secretion in a normal endothelial cell line, but not in a cancer cell line. In conclusion, this indicates that FKBPL is a potent secreted anti-angiogenic protein, and is essential for normal 1 physiological development. As well as being an anti-angiogenic drug with potential for use in cancer treatment, ALM201 also has the potential to reduce weight gain and to normalise blood glucose in patients deficient in FKBPL, opening up further opportunities for future study.

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15

Mathioudakis, Nikolaos. "Etudes fonctionnelles sur le composant de la voie des piRNA TDRD1." Phd thesis, Université de Grenoble, 2012. http://tel.archives-ouvertes.fr/tel-00907417.

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Les ARN interagissants avec Piwi (ARNpi) sont des petits ARN non-codants qui sont exprimes dans la ligne grrminale des animaux. Ils interagissent avec les proteines de la branche Piwi de la famille des Argonautes en formant des complexes des ribonucleproteines impliques dans le maintien de l'intégrité du génome. La region N-terminale des quelques proteines Piwi contiennent symetriquement des arginines diméthylées. Il est considere que ce status symmetrique de la dimethylation est responsable du recrutement des proteines possédant des domaines Tudor (TDRDs). Ces domaines peuvent avoir un role comme platforme pour medier les interactions entre les proteines de la voie de l'ARNpi. Nous avons mesure indivindiuellemnt l'affinite de liaison des quatres domaines etendus Tudor (TD) de la proteine murine TDRD1 pour les trois differents peptides de la protein murine Mili qui contiennent de la methyl-arginine. Les resultats montrent une preference des TD2 et TD3 pour les peptides consecutives Mili alors que TD4 et TD1 ont une affinite plus bas et plus faible respectivement pour tous les peptides. Ces observations ont ete confirmees par des experiences pull-down en utilisant des proteines Piwi endogenes et des proteines-interagissent avec Piwi. L'affinite de TD1 pour les peptides qui contiennent de la methyl-arginine peut etre restoree par une seul mutation ponctuelle dans la cage aromatique pour revenir a la sequence consensus. La structure de cristal de la proteine TD3 lie au peptide methyle Mili montre une orientation inattendue de la peptide de liaison et de la chaine latérale de l'arginine methyle dans la cage aromatique. Finalement, le model SAXS des quatres domains tandem Tudor de TDRD1 revele une forme de la proteine flexible et elongee. Globalement, les resultats montrent que la proteine TDRD1 peut accommoder des differents peptides des differentes proteines et ainsi de fonctionner comme une protéine d'échafaudage dans la voie de l'ARNpi. La proteine FKBP6 (FK506 Binding Protein) a ete recemment identifiee comme un nouvel facteur interagissent dans la voie de l'ARNpi. FKBP6 est constituee d'une domaine d'isomerase FK et une domaine de tetratricopeptide (TPR). Une perte de la Fkbp6 conduit a la de -repression des transposons et a la sterilite masculine des souris. Le domaine TPR est implique dans l'interaction avec la proteine chaperone Hsp90 et le domaine FK est une isomerase inactive qui a ete evolue a une module structurale. En effectuant des exepriences biochimiques preliminaires nous avons identifie la region N-terminal du domaine MYND de TDRD1 comme le partenaire d'interaction du domaine FK de la FKBP6. Nous proposons que la proteine TDRD1 est une plateforme moleculaire qui reconnait des marques de methylation de MILI et elle recrute FKB6 pour promouvoir la formation d'un complexe indispensable pour la fonction de la voie de l'ARNpi.

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Grimley, Joshua Stuart. "The synthesis of FKBP ligands and the first total synthesis of phomopsin B /." May be available electronically:, 2007. http://proquest.umi.com/login?COPT=REJTPTU1MTUmSU5UPTAmVkVSPTI=&clientId=12498.

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McAlpine, Kerry Elizabeth. "Characterisation of the novel hsp90 interacting protein FKBPL and its potential role in steroid receptor complexes." Thesis, Queen's University Belfast, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.484996.

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The FKBPL protein was recently identified as an hsp90 interacting protein and shares significant homology to the immunophilins FKBP52 and cyclophilin 40. The FKBPs are involved in many cellular processes, one of the most documented being their role in hsp90-steroid 'receptor complexes. It was therefore thought logical to investigate a potential role for FKBPL in these complexes. The main aims were to evaluate potential interactions between FKBPL the glucocorticoid receptor (GR) and dynamitin. The functional role played by FKBPL would be addressed in overexpression studies. Since a single nucleotide polymorphic variant and a 12 bp insertion mutant of FKBPL had been identified, the ability of these variants to interact and function within steroid receptor complexes was also evaluated. Finally. a small study was carried out to determine if a correlation existed between the frequency of the FKBPL SNP and the incidence of cancer. Co-localisation studies revealed that FKBPL co-Iocalisea with the glucocorticoid receptor, dynamitin and tubulin. Interactions of FKBPL and its variants with dynamitin was verified using the biomolecular fluorescence complementation assay. furthermore, the cytoplasmic localisation of the interaction with hsp90 was determined in this assay. This assay also confirmed interactions of the FKBPL variants with hsp90. Interactions between endogenous FKBPL and polymorphic FKBPL with GR/dynamitin were confirmed by co-immunoprecipitation. These data suggested a role for FKBPL in steroid hormone receptor complexes. Co-localisation of GR and FKBPL was examined after treatment with the GR ligand dexamethasone. Both proteins translocated from the cytoplasm to the nucleus of DU145 cells within 10 min, indicative of retrograde transport. FKBPL overexpression was found to decrease GR protein levels and transactivity in L132 cells, and increase GR protein levels in DU145 cells. FKBPL overexpression also caused a dexamethasone . dose dependent increase in GR transactivity in DU145 cells. These data suggest FKBPL is involved in steroid rec~ptor complexes and modulates GR protein levels and signalling. Finally, we demonstrated that although the homozygous SNP variant was more prevalent in DNA from endometrial cancer and HNPCC patients, compared to controls, it \Vas not significant.

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O'leary, John Clarence. "The Role of Molecular Chaperones in the Etiology and Treatment of Psychiatric Diseases in the Elderly." Scholar Commons, 2013. http://scholarcommons.usf.edu/etd/4737.

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The elderly are at increased risk for developing psychiatric diseases, which include Alzheimer's disease, depression, anxiety and suicide. The probability of multiple disease comorbidity is also increased in the elderly. At the cellular level, the loss of protein homeostasis is often at the root of disease emergence, and thus the scientific community is searching for ways to help maintain this balance. A vast group of proteins that are paramount to balancing and counterbalancing protein levels is the molecular chaperone protein group, which has evolved a tremendous variety of functions in the cell. They aid in protein trafficking, folding, receptor signaling, neurotransmission, vesicle forming and fusion, protein degradation, and apoptosis, among other activities. Despite their best efforts, disease still ensues, but because of their vast number and multiple abilities, it may be possible to modulate these proteins as a way to treat and prevent disease. Chaperones are of particular interest in diseases of aging, because chaperone induction and effectiveness is reduced with age. In addition, many diseases of the elderly are brought on by aberrant protein accumulation, like Alzheimer's disease. As a result, the hypothesis of this dissertation is whether the modulation of molecular chaperones changes disease pathology. A molecular chaperone family that is important to protein degradation is the Hsp70 chaperone complex. Hsp70 proteins have specialized function depending on cell type and cellular compartment, but Hsp70 proteins are very important for protein synthesis and degradation. As a result, they are in a position to contribute to the regulation of proteins that become aberrant. In recent years scientific literature has indicated that compounds that inhibit the enzymatic ATP hydrolysis of these proteins promote tau degradation, which accumulates in Alzheimer's disease. Alzheimer's disease is the sixth leading cause of death in the U.S., it is a progressive neurodegenerative disease, and is caused by the aberrant accumulation of the amyloid beta and tau proteins. Here, we show that treatment with the Hsp70 inhibitor methylene blue, reduces tau, saves neurons, and restores cognition, in a mouse model of tau accumulation (rTg4510). Cognitive rescue occurred despite a severe tangle load, equal to control treated tau transgenic mice. This study shows that reducing soluble tau can restore cognition, reducing tangles is not necessarily to ameliorate cognition, and saving neurons is not sufficient to increase cognition if they are burdened with soluble tau. This work shows that methylene blue does not affect the the number of tau tangles in this model, as suggested by in vitro data. It also suggests that further work into the development of Hsp70 ATPase inhibitors may find success in alleviating the soluble tau burden found in Alzheimer's disease. The co-chaperone FKBP5 is also of extreme importance, not because it is essential, but because research has implicated this protein with a host of psychiatric diseases. Single nucleotide polymorphisms in this gene, which increase the levels of FKBP5, interact with averse traumatic events to enhance the likelihood of developing mood and anxiety disorders, including major depressive disorder, post-traumatic stress disorder, bipolar disorder, and suicide. Moreover, we have found that FKBP5 protein levels increase with age in the human brain, increasing the risk for the elderly of developing disease if exposed to traumatic stress. Here, we tested the hypothesis that FKBP5 negatively regulates resilient behavior. We found that FKBP5 levels increase with age in the wild type mouse brain, and that wild type mice display reduced resiliency with age. FKBP5-/- mice, on the other hand, show enhanced resiliency to stress at all ages tested, and are protected from aging-induced despair. At the molecular level, FKBP5 is a robust inhibitor of the glucocorticoid receptor, which is responsible for the shut-off of the hypothalamic-pituitary-adrenal axis. In addition, excess glucocorticoid levels in the blood is a robust marker of psychiatric disease. Consequently, FKBP5 may be causing disease through enhanced levels of glucocorticoids. FKBP5-/- mice display reduced corticosterone after stress. Moreover, corticosterone production increases with age, and FKBP5-/- mice are protected from this increase. These studies are the first to show that reducing the levels of FKBP5 is a promising therapeutic option for the treatment of mood disorders in the elderly, resiliency naturally declines with age due to FKBP5, corticosterone levels after stress rise due to FKBP5, and that the ablation of this gene increases resiliency and prevents aging- induced despair. As a whole, these data show that the modulation of chaperone proteins has the potential for developing new therapies for the treatment of psychiatric diseases of the elderly.

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Nelson, Laura. "Evaluating the prognostic and predictive potential of FKBPL and associated proteins as biomarkers in breast and ovarian cancer." Thesis, Queen's University Belfast, 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.677957.

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Despite adjuvant systemic therapies improving breast cancer survival rates, some patients are over- or under-treated. This is particularly problematic for the management of early stage ER+/LN- breast cancers. Identifying patients at a higher risk of relapse for whom additional adjuvant chemotherapy is necessary, remains a significant challenge. The primary focus of this thesis was to evaluate the prognostic potential of FKBPL within breast TMA cohorts, and as part of a meta-analysis. FKBPL was shown to be an independent prognostic marker, which is able to predict breast cancer specific survival in ER positive, node positive patients. I As many prognostic tests now focus on the inclusion of multiple markers, the prognostic ability of two FKBPL-associated proteins, phospho-ERα and p21, were also assessed, however both failed to correlate with survival. In an attempt to evaluate the prognostic potential of additional FKBPL-associated proteins, the relationship between FKBPL and an FKBPL-interacting protein, USP19, was characterised in breast cancer cell lines. After an interaction between the two proteins was confirmed, subsequent analysis identified a role for USP19 in the deubiquitination and stabilisation of FKBPL. USP19 was shown to positively regulate FKBPL protein expression in breast cancer cell lines, functionally suppressing breast cancer cell proliferation . . ALM201, an anti-angiogenic peptide based on FKBPLs active anti-angiogenic domain, is soon to enter Phase 1111 clinical trials in ovarian cancer patients. Therefore, the current study also aimed to evaluate FKBPL's prognostic potential within an ovarian cancer TMA cohort, with the potential to utilize the FKBPL biomarker as a companion diagnostic. Unfortunately, FKBPL was not prognostic in the ovarian cancer setting. In conclusion, FKBPL has the ability to further stratify ER+/LN- breast cancer patients, identifying patients who may benefit from additional adjuvant chemotherapy. Validating the prognostic potential of USP19, within the breast cancer setting might prove beneficial to further sensitise the marker.

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Kollmannsberger, Lorenz Korbinian [Verfasser], and Haralabos [Akademischer Betreuer] Zorbas. "The role of FKBP5 in transcriptional regulation and in shaping cellular pathways of psychopharmaca action / Lorenz Korbinian Kollmannsberger. Betreuer: Haralabos Zorbas." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2016. http://d-nb.info/1099910536/34.

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Winkler, Britta [Verfasser], Birgit [Akademischer Betreuer] Harbeck, and Christian [Gutachter] Schmidt. "Pilotstudie: FKBP5 Methylierung als Biomarker der Cortisolexposition bei gesunden Probandinnen und Probanden / Britta Winkler ; Gutachter: Christian Schmidt ; Akademischer Betreuer: Birgit Harbeck." Lübeck : Zentrale Hochschulbibliothek Lübeck, 2020. http://d-nb.info/1207429066/34.

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22

Pöhlmann, Max [Verfasser], and Mathias [Akademischer Betreuer] Schmidt. "Unraveling the functional contribution of Fkbp5 to stress vulnerability : shaking up molecular links between stress and disease / Max Pöhlmann ; Betreuer: Mathias Schmidt." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2020. http://d-nb.info/1206096578/34.

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23

Beintner, Madita [Verfasser], Bertram [Akademischer Betreuer] [Gutachter] Müller-Myhsok, and Thomas A. [Gutachter] Meitinger. "Dexamethason-stimulierte FKBP5-Genexpression und ACTH- und Cortisolsuppression im Zeitverlauf / Madita Beintner ; Gutachter: Bertram Müller-Myhsok, Thomas A. Meitinger ; Betreuer: Bertram Müller-Myhsok." München : Universitätsbibliothek der TU München, 2016. http://d-nb.info/1119318645/34.

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Stamm, Thomas J., Carina Rampp, Katja Wiethoff, Julia Stingl, Rainald Mössner, Grace O'Malley, Roland Ricken, et al. "The FKBP5 polymorphism rs1360780 influences the effect of an algorithm-based antidepressant treatment and is associated with remission in patients with major depression." Sage, 2016. https://tud.qucosa.de/id/qucosa%3A35633.

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Objective: The FKBP5-gene influences the HPA-system by modulating the sensitivity of the glucocorticoid receptor (GR). The polymorphism rs1360780 has been associated with response in studies with heterogeneous antidepressant treatment. In contrast, several antidepressant studies with standardized antidepressant treatment could not detect this effect. We therefore compared patients with standardized vs naturalistic antidepressant treatment to (a) investigate a possible interaction between FKBP5-genotype and treatment mode and (b) replicate the effect of the FKBP5-genotype on antidepressant treatment outcome. Methods: A total of 298 major depressive disorder (MDD) inpatients from the multicentred German project and the Zurich Algorithm Project were genotyped for their FKBP5 status. Patients were treated as usual (n=127) or according to a standardized algorithm (n=171). Main outcome criteria was remission (Hamilton Depression Rating Scale-21<10). Results: We detected an interaction of treatment as usual (TAU) treatment and C-allele with the worst outcome for patients combining those two factors (HR=0.46; p=0.000). Even though C-allele patients did better when treated in the structured, stepwise treatment algorithm (SSTR) group, we still could confirm the influence of the FKBP5-genotype in the whole sample (HR=0.52; p=0.01). Conclusions: This is the first study to show an interaction between a genetic polymorphism and treatment mode. Patients with the C-allele of the rs1360780 polymorphism seem to benefit from a standardized antidepressant treatment.

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Rampp, Carina [Verfasser]. "Einfluss eines Polymorphismus im FKBP5-Gen (rs1360780) auf Antidepressivatherapie sowie auf den Effekt einer algorithmusgestützten Behandlung : eine Studie aus dem German Algorithm Project / Carina Rampp." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2014. http://d-nb.info/1046832735/34.

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Monneau, Yoan. "Etude des modifications post-traductionnelles des histones : l’analyse structuro-fonctionnelle d'une peptidyl-prolyl isomérase et la production semi-synthétique d’une protéine acétylée." Thesis, Bordeaux 2, 2011. http://www.theses.fr/2011BOR21900/document.

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L'unité structurale de la chromatine, nommée nucléosome, est composée d'un double brin d'ADN enroulé autour d'un octamère d'histone, et subit une pléthore de modifications post-traductionnelles. Les conséquences biologiques de l’acétylation des lysines et de l’isomérisation des liaisons peptidyl-prolyl ont été étudiées à travers une analyse à l’échelle atomique par RMN de systèmes d'intérêt reconstitués in vitro. Les liaisons peptidyl-prolyl du domaine N-terminal de l'histone H3 sont substrats in vitro d’une isomérase chez S. cerevisiae nommée Fpr4p, laquelle exerce un contrôle catalyse-dépendant de la transcription. La résolution de la structure du domaine catalytique de Fpr4p, à partir de contraintes géométriques mesurées par RMN, révéla un domaine canonique de la famille FKBP (FK506-binding protein). Grâce à l'analyse de la séquence primaire et aux expériences RMN, nous proposons un modèle structural préliminaire de Fpr4p entière. L'analyse fonctionnelle est réalisée grâce à trois décapeptides construits à partir de la séquence primaire de H3 chez S. cerevisiae. Ils sont tous substrats de Fpr4p et la catalyse est équivalente pour Pro16 et Pro30. La proportion à l'équilibre du conformère cis fut déterminée pour les trois peptides et celle-ci n'est pas affectée par l'activité catalytique de Fpr4p. Les structures en solution des substrats en conformation trans ont été résolues par spectroscopie RMN, et seront utilisées pour des appariements moléculaires in silico sur le domaine catalytique de Fpr4p. Pour étudier le rôle biologique de l'acétylation des histones, une méthodologie de production de protéines acétylées a été développée. Le protocole repose sur la mutation d'une lysine en cystéine d'une protéine recombinante, suivie d'une alkylation contrôlée exploitant la nucléophilie du groupe thiol préalablement introduit. La production de l'agent alkylant adéquat est simple, rapide, réalisable dans un laboratoire de biologie et permet différents marquages isotopiques du groupe acétyle. L'alkylation d'une protéine repliée fut réalisée avec succès en conditions natives. Le dimère d'histone H2A-H2B, un intermédiaire de l'assemblage du nucléosome et siège d'acétylation in vivo, fut reconstruit in vitro. Les déplacements chimiques des domaines N et C-terminaux de H2A sont cohérents avec un état intrinsèquement déstructuré bien que leurs dynamiques moléculaires ne soient pas équivalentes
The structural unit of chromatin, the nucleosome, is composed of double-stranded DNA wrapped around a histone octamer and is subject to a plethora of post-translational modifications. The biological consequences of peptidyl-prolyl isomerization and lysine acetylation were investigated at atomic scale through analysis of in vitro reconstituted systems by NMR. Peptidyl-prolyl bonds of histone H3 N-terminal domain are substrates in vitro of an isomerase from S. cerevisiae named Fpr4p, which underlies transcriptional control dependent on its catalytic activity. The solution structure of the catalytic domain of Fpr4p was calculated based on restraints from NMR spectroscopy, and reveals a canonical catalytic domain belonging to the FK506-binding protein (FKBP) family. Based on primary sequence analysis and NMR experiments, a preliminary structural model of full length Fpr4p is also presented. Functional analyses were performed with three decapeptides designed from the primary sequence from the N-terminal tail of S. cerevisiae histone H3. All three constitute substrates of Fpr4p, with equivalent catalysis observed for Pro16 and Pro30. The equilibrium proportion of the cis-proline conformer has been determined for all three decapeptides, and these populations are unaffected by Fpr4p catalytic activity. Structural ensembles of the substrates with proline in the trans conformation were determined by using NMR spectroscopy, and will be subsequently used for in silico molecular docking onto Fpr4p. To study a second form of histone regulation, a semi-synthetic method to produce acetylated protein was developed. The protocol relies on the site-specific mutation of lysine to cysteine in recombinant proteins followed by controlled alkylation thanks to nucleophilicity of the introduced thiol. The production of the required alkylation reagent is easy, quick, and suitable for biology laboratory and allows diverse isotopic labeling within the acetyl group. Alkylation of folded proteins has also been achieved in native conditions. As one target of acetylation in vivo, the histone H2A-H2B dimer is an intermediate of nucleosome assembly and was reconstituted in vitro. Chemical shift values of the N- and C-terminal domains of H2A are in agreement with an intrinsically disordered state although they display differences in dynamic mobility

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Rosa, Eva-Maria [Verfasser], Oliver [Akademischer Betreuer] Kratz, and Oliver [Gutachter] Kratz. "Stereologische Quantifizierung NPY-positiver Zellen und Expressionsanalyse von Fkbp5 und Glucocorticoid-Rezeptor in verschiedenen Gehirnregionen von Stress-resilienten DPP4-defizienten Ratten / Eva-Maria Rosa ; Gutachter: Oliver Kratz ; Betreuer: Oliver Kratz." Erlangen : Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 2020. http://d-nb.info/1215343299/34.

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28

Edvardsson, Anna. "Peptidyl-prolyl cis-trans Isomerases in the Chloroplast Thylakoid Lumen." Doctoral thesis, Linköping : Univ, 2007. http://www.bibl.liu.se/liupubl/disp/disp2007/med983s.pdf.

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Savic, Neda. "Insights into the comparative biological roles of S. cerevisiae nucleoplasmin-like FKBPs Fpr3 and Fpr4." Thesis, 2019. http://hdl.handle.net/1828/11464.

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The nucleoplasmin (NPM) family of acidic histone chaperones and the FK506-binding (FKBP) peptidyl proline isomerases are both linked to chromatin regulation. In vertebrates, NPM and FKBP domains are found on separate proteins. In fungi, NPM-like and FKBP domains are expressed as a single polypeptide in nucleoplasmin-like FKBP (NPL-FKBP) histone chaperones. Saccharomyces cerevisiae has two NPL-FKBPs: Fpr3 and Fpr4. These paralogs are 72% similar and are clearly derived from a common ancestral gene. This suggests that they may have redundant functions. Their retention over millions of years of evolution also implies that each must contribute non-redundantly to organism fitness. The redundant and separate biological functions of these chromatin regulators have not been studied. In this dissertation I take a systems biology approach to fill this knowledge gap. First, I refine the powerful synthetic genetic array (SGA) method of annotating gene-gene interactions, making it amenable for the analyses of paralogous genes. Using these ‘paralog-SGA’ screens I define distinct genetic interactions unique to either Fpr3 or Fpr4, shared genetic interactions common to both paralogs, and masked genetic interactions which are direct evidence for processes where these enzymes are functionally redundant. I provide transcriptomic evidence that Fpr3 and Fpr4 cooperate to regulate genes involved in polyphosphate metabolism and ribosome biogenesis. I identify an important role for Fpr4 at the 5’ ends of protein coding genes and the non-transcribed spacers of ribosomal DNA. Finally, I show that yeast lacking Fpr4 exhibit a genome instability phenotype at rDNA, implying that this histone chaperone regulates chromatin structure and DNA access at this locus. Collectively, these data demonstrate that Fpr3 and Fpr4 operate separately, cooperatively and redundantly to regulate a variety of chromatin environments. This work is the first comprehensive and comparative study of NPL-FKBP chaperones and as such represents a significant contribution to our understanding of their biological functions.
Graduate

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Cree, Tabitha. "Investigating the role of FK506 binding protein 25 in cell proliferation and differentiation." Thesis, 2021. https://vuir.vu.edu.au/42901/.

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Peptidyl prolyl isomerases (PPIase) are a class of enzymes that are required to catalyse the conversion of proline residues from cis to trans conformation. There are several classes of PPIase molecules, including parvulins, cyclophilins, and FK506 binding proteins (FKBPs). Among these PPIase molecules each class contains a conserved PPIase domain that facilitates protein to protein interactions. These PPIase molecules have diverse functions in cellular function and disease progression. FKBPs are a group of immunophilin molecules that are known to interact with immunosuppressant molecules FK506 and rapamycin to stop the immune response and inhibit mTOR, respectively. The structure and function of FKBPs is diverse, these proteins act to facilitate protein to protein interactions, act as co-chaperones, translocate throughout the cell in response to stress events, and bind to DNA. Importantly, FKBPs have been implicated in the pathogenesis of cancer, largely through their roles in co-chaperoning hormone receptors in hormone responsive cancers i.e. breast and prostate cancers. Of particular interest, FKBP25, a 25kDa protein that consists of two functional domains, an N terminal basic helix–loop–helix and C terminal PPIase domain. FKBP25 is known to be involved in protein folding, cytoskeletal dynamics, DNA damage repair, double stranded RNA binding, interacting with the pre-ribosome, and cellular stress responses. Despite the variety of roles that FKBP25 is known to play, there is limited research regarding FKBP25 role in disease and cell differentiation. To address this, initial studies investigated the role of FKBP25 in breast cancer progression and epithelial to mesenchymal transition (EMT). Here it was found that FKBP25 protein expression is reduced in both mesenchymal breast cancer cell types, including BT-549, Hs578t, MDA-MB-231. To further understand the potential role of FKBP25 in breast cancer pathogenesis, a variety of mutations that contribute to malignant transformation were examined. Here it was found that the oncogenic mutations, that are associated with growth pathways in fact increased FKBP25 expression. However, in an epidermal growth factor mediated model EMT in MDA- MB-468 breast cancer cells, it was identified that FKBP25 protein expression was reduced. This implies that the loss of FKBP25 protein expression may be required for de-differentiation and progression of cancer cells. As such, it was hypothesised that FKBP25 protein expression was correlated with the level of cellular differentiation. To examine this hypothesis, next a model of mesenchymal to epithelial transition (MET) was analysed. The C2C12 model of myogenesis to study the role of FKBP25 in an MET-like example of cell differentiation. Previous studies have identified that FKBP25 is the most highly expressed FKBP in skeletal muscle and is expressed in the top 10% of the skeletal muscle proteome. Here it was identified that in proliferative myoblasts there is a higher level of FKBP25 protein expression compared to that of post mitotic myotubes. This was further demonstrated in a model of C2C12 quiescence where it was demonstrated that upon removal from the cell cycle, myoblasts accumulate greater levels of FKBP25 protein expression, which is then reduced upon re-entry to the cell cycle. Interestingly, this trend was not observed in human primary myoblasts, however, was identified in human rhabdomyosarcoma cells which may be due to the presence of p53 and MyoD mutations. Furthermore, in vivo models of muscle plasticity were examined to assess the impact of FKBP25 on skeletal muscle regeneration considering FKBP25 is the most highly expressed FKBP in mature skeletal muscle. Here it was discovered that FKBP25 protein expression is increased in models of regeneration including, chronic mechanical loading, murine muscular dystrophy (mdx), and denervation. It is hypothesised that this was observed due to extensive cytoskeletal remodelling to repair structural damage caused by hypertrophy and atrophy of fibres. Next, we examined the impact of FKBP25 knockdown (25KD) on cell biology and function of MDA-MB-468 and C2C12 cells. 25KD cells were developed using doxycycline inducible SMARTvector (Dharmacon, CO, USA) short hairpin RNA technology. After confirming adequate 25KD, it was observed that in both cell lines 25KD resulted in an increase in proliferation compared to respective non-targeting (NT) cells. Furthermore, in MDA-MB-468 cells, it was observed that there were no changes to invasion outgrowth or migration in vitro. However, it was demonstrated that 25KD resulted in decreased anchorage dependent growth, which could be explained by alterations to cytoskeletal stability. Conversely, in C2C12 myoblasts it was found that 25KD resulted in a significant increase in wound healing migration. Upon investigation of myogenic regulatory factor expression in differentiated 25KD myotubes it was revealed that there were no changes in protein expression. Furthermore, upon measurement of fibre diameter and fusion index it was found that there were no discernible changes to myotube formation. Finally, the influence of 25KD on tubulin regulation and dynamics was assessed. Initially, the presence of microtubule (MT) post-translational modifications was assessed, including detyrosination and acetylation which are associated with MT stability. Both C2C12 and MDA-MB-468 25KD cells showed no changes to stabilising modifications. Similarly, upon examination of MT stabilising protein stathmin, both C2C12 and MDA-MB-468 25KD showed no change to stathmin expression. After this, the impact of 25KD on tubulin polymerisation under control and paclitaxel treated (induction of maximal polymerisation) conditions was explored. However, here no differences in MT polymer content was found in either 25KD in either C2C12 or MDA- MB-468 cells. In conclusion, this thesis has examined the potential role of FKBP25 in cell differentiation and de-differentiation in EMT and MET-like models. It was found that FKBP25 is required for some cell processed including proliferation, anchorage dependent growth, and migration. It was hypothesised that this was a result of cytoskeletal reorganisation and altered MT dynamics, however, this was unable to be demonstrated. Further studies should further examine the impact of 25KD on MT dynamics using methods less prone to error. Nonetheless, FKBP25 was demonstrated to have a role in cell proliferation and differentiation. Maintenance of FKBP25 protein in both cancers and skeletal muscle could help to preserve epithelial-like phenotype and maintain structural integrity, respectively.

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31

Pak, Kei Chan. "The Role of FKBP5 in Influenza Virus Infection." Thesis, 2010. http://hdl.handle.net/1807/24547.

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FK506 binding protein 5 (FKBP5) is a peptidyl propyl cis-trans isomerase that has been shown to interact with cellular immune pathways such as calcineurin and NF-κB. During an influenza infection, FKBP5 is up-regulated at the lung in an in vivo ferret infection model, yet the effect of FKBP5 on influenza replication and immune response is not understood. An in vitro model of human alveolar epithelial cell line A549 was established to study the cause and the function of FKBP5 up-regulation during an influenza infection. In this in vitro model, FKBP5 was not up-regulated by influenza replication, but instead it was up-regulated when A549 cells were treated with glucocorticoid. FKBP5 up-regulation did not have any effect on rate of influenza replication. However, FKBP5 up-regulation mediated the suppressive effect of glucocorticoid on pro-inflammatory cytokine production, since FKBP5 knock-down by siRNA increased cytokine production in the presence of glucocorticoid. Overall, the results suggested that the up-regulation of FKBP5 is a physiological response of lung cells to the increase of glucocorticoid during influenza infections, which facilitates the suppressive effect of glucocorticoid on pro-inflammatory cytokine production.

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Yang, Ting-Ting Ou, and 歐陽婷婷. "Regulation of Fkbp5 Expression by Glucocorticoid and Hypoxia in Cortical Neurons." Thesis, 2010. http://ndltd.ncl.edu.tw/handle/24536791509588907552.

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碩士
臺北醫學大學
醫學科學研究所
98
Glucocorticoid receptor (GR) is a ligand-activated transcription factor, activated upon binding to glucocorticoids (GCs) when the hypothalamic-pituitary-adrenal (HPA) axis is aroused by stress. FK506 binding protein 5 (Fkbp5) and 5-HT1A receptor (Htr1a) are two of the GR-downstream genes, which were found related to depression in patients. Fkbp5 encodes FKBP51 protein chaperoned by Heat shock protein (HSP90) to form a negative feedback loop for the regulation of GR sensitivity. Recent studies revealed that the serum level of FKBP51 in patients with depression seems to associate with the sensitivity to the anti-psychotic drug treatment. However, the role of FKBP51 in the etiology of depression and the stress-related mental disorders remains unknown. In the present study, we examined the effects of GC, and in combination of hypoxic stress, on the expression of Fkbp5 and 5-HT1A receptor in primary cultured cortical neurons at 10 days-in-vitro (10 DIV). The results show that 12-h treatment with GR agonist dexamethasone (Dex), a synthetic glucocorticoid, increased the expressions of both Fkbp5 and Htr1a in primary cultured cortical neurons. The Dex-increased Fkbp5 was suppressed by cobalt chloride that induces chemical hypoxia. Interestingly, using prolonged Dex treatment (48-96 h) onto cortical neurons to simulate chronic stress in the brain elevated both Fkbp5 and Htr1a gene expression, with the Fkbp5 upregulation showing a two-phase induction profile. However, the prolonged Dex treatment showed sustained reduction of GR proteins, and increased responsiveness to the depolarizing agent (high K+)-induced intracellular calcium increase. Together, the results suggest that both acute and prolonged GC treatments upregulate Fkbp5 expression, which may negatively feedback the GR expression in cortical neurons. Hypoxia seems to interfere with this feedback mechanism by inhibiting the GC-induced Fkbp5 expression. Prolonged GC treatment reverses the acute GC repression of 5-HT1A receptor expression, which may cause the changes in the cortical excitability during chronic stress.

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MAZURKA, RAEGAN. "Interaction of Polymorphisms in the FKBP5 Gene & Childhood Adversity on the Cortisol Response to a Psychosocial Stress Task in Adolescents and Young Adults." Thesis, 2013. http://hdl.handle.net/1974/8250.

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Childhood adversity is often associated with devastating physical, cognitive, and psychosocial outcomes, and is a major public health problem in terms of its prevalence and economic cost. Childhood adversity is associated with increased risk for psychopathology, as well as with dysregulation of the neurobiological stress response. An additional factor known to alter neuroendocrine functioning and increase psychopathology risk is polymorphisms within the FKBP5 gene. The goal of the current study was to examine the gene-environment interaction of childhood adversity and variation in the FKBP5 gene on the cortisol response to a psychosocial stress task (i.e., the Trier Social Stress Test). The final sample consisted of 90 depressed and non-depressed adolescents and young adults (11 - 21 years). Childhood adversity was assessed using the Childhood Experience and Abuse Scale (CECA; Bifulco et al., 1994), and was defined as the presence versus absence prior to 18 years of age of severe physical, sexual, or emotional abuse or neglect, witness to domestic discord/violence, or peer-perpetrated bullying. Participants were genotyped at the rs1360780 site of the FKBP5 gene and grouped according to whether they had at least one risk T allele (i.e., TT or TC genotype versus the CC genotype). Controlling for depression and anxiety psychopathology, I found a significant interaction of FKBP5 and childhood adversity status such that individuals with the FKBP5 risk allele (i.e., TT or TC genotype) and a history of childhood adversity showed a distinct cortisol response pattern characterized by decreasing cortisol from baseline and less cortisol output compared to individuals without childhood adversity. This relationship was specific to the experience of severe adversity and appeared to be strongest when adversity was defined as witnessing domestic discord/violence. These results are consistent with a diathesis-stress model in which the FKBP5 risk allele leaves individuals vulnerable to neurobiological dysregulation in the face of severe adverse experience in childhood. The implications of this research for understanding stress-related psychopathology and the limitations of this gene-environment interaction design are discussed.
Thesis (Master, Psychology) -- Queen's University, 2013-09-05 11:24:45.764

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Malone, Jenna Moira. "Analysis of signal pathway protein-protein interactions during biotic and abiotic stress." 2009. http://hdl.handle.net/2440/60985.

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The overall objective of the work described in this thesis was to characterise the three genes Hv14.3.3c, HvMAPKK1 and HvFKBP41, in terms of a role in defence and stress response signalling. These genes had previously been found to be differentially expressed in compatible versus incompatible interactions of barley with the fungus Rhynchosporium secalis, suggesting a possible role in the plant defence response, while current literature suggests these genes may also play a role in signal transduction, possibly under a broad range of stresses, including abiotic as well as biotic. Two main approaches were undertaken to characterise gene function: expression analysis and the identification of protein-protein interactions. To facilitate expression analysis, full length cDNA fragments of each gene were first obtained using bioinformatics, RACE and genomic walking techniques. Expression was then investigated using quantitative real-time RT-PCR. The results of the expression analysis confirmed that the candidate genes were in fact differentially expressed during infection, suggesting a role in the defence response of barley against R. secalis. Analysing their expression in the context of other stresses and treatments, namely frost, drought and ABA, indicated their role may not be limited only to biotic stress, but include abiotic stress as well. To investigate the possibility that these genes are involved in signalling during the defence response, protein-protein interaction techniques such as yeast two-hybrid and affinity pulldowns were used to identify interacting proteins in an attempt to place the genes within a known signalling network and build and extend on these networks. Y2H screening was used successfully to identify two putative interactors of Hv14.3.3c; an EPSP (5-enolpyruvylshikimate-3-phosphate) synthase and a putative wound-induced protein, and two interactors of HvFKBP41; a Rab-type GTPase and the same wound-induced protein. From what is known about the function of these genes in the literature, they fit well with a role in stress response signalling and the potential to be involved in signalling networks with the candidate gene products and also with each other. Through the trial of many different affinity pulldown techniques, a method for identifying interacting proteins from plant extracts was successfully established, however, issues with protein identification meant that interacting proteins were not identified using this technique. Steps were then made towards confirming the interactions identified using the Y2H system. Full length cDNA sequences of the identified interactors were obtained and expression analysis performed, in the aim of investigating co-expression patterns between the genes encoding the interacting proteins and the three candidate genes, to support a potential interaction. To confirm the Hv14.3.3c-HvEPSP interaction, co-immunoprecipitation and BRET were then used, however confirmation was unsuccessful due to issues with non-specific binding in co-immunoprecipitation and technical issues trying to establish the BRET analysis system in barley. In summary, the results of this study place the candidate genes Hv14.3.3c, HvMAPKK1 and HvFKBP41 as players in signal transduction during the plant defence/stress response. With the identification of previously uncharacterised protein interactions, some progress has also been made towards placing these genes within known signalling networks and identifying potential downstream genes that could possibly play a more specific role in defence response signalling and therefore be potential targets for the generation of resistant or stress tolerant plants.
Thesis (Ph.D.) -- University of Adelaide, School of Agriculture, Food and Wine, 2009

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35

Gawlik, Micha. "Assoziations- und Haplotypuntersuchung der Kandidatengene DAOA und FKBP5 bei Patienten mit manisch-depressiver Erkrankung, mit monopolarer Depression oder zykloider Psychose." Doctoral thesis, 2007. https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-23798.

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Im Rahmen dieser Studie sollte die Frage beantwortet werden, ob sich einzelne SNPs oder Haplotypen als biologische Marker affektiver Psychosen identifizieren lassen. Hierfür sollten Assoziations- und Haplotypuntersuchung an zwei Kandidatengenen, FKBP5 und G72 DAOA/G30, mit unterschiedlichen pathophysiologischen Theorien, durchgeführt werden. Das auf der Kortisolhypothese basierende Kandidatengen FKBP5 liegt auf dem Chromosom 6 p21 und stellt ein wichtiges Regulatorprotein für den Glukokortikoid- Rezeptor (GR) dar. In FKBP5 wurden drei SNPs mit einem schnelleren Ansprechen auf Antidepressiva assoziiert gefunden: rs4713916 in der vermuteten Promoterregion, rs1360780 im 2. Intron und rs3800373 im nicht translatiertem 3Ende (Binder et al. 2004). Die vorbeschriebenen Polymorphismen sollten in einem unabhängigen Kollektiv auf Assoziation mit affektiven Psychosen untersucht werden, um eine Rolle von FKBP5 bei der Ätiopathogenese affektiver Psychosen zu überprüfen oder einen Einfluss auf verschiedene Variable des Krankheitsverlaufs zu bestätigen. In unserer Studie mit 248 Fällen und 188 Kontrollen unterschieden sich die untersuchten SNPs in FKBP5, rs4713916, rs1360780 und rs3800373 in ihrer Verteilung nicht bei Erkrankten und Gesunden. Den einzigen signifikanten Hinweis für eine Assoziation mit affektiven Erkrankungen bot der Risikophaplotyp G-C-G mit einer Odds Ratio von 6,4, der jedoch nur bei 2,1% der Fälle vorkam. Auch zeigte sich kein Zusammenhang mit den untersuchten klinischen Parametern. Die Untersuchungsergebnisse können somit einen wesentlichen Beitrag von FKBP5 für die depressive Erkrankung nicht belegen. Es erscheint daher fraglich, ob Polymorphismen in FKBP5 als biologische Marker affektiver Psychosen dienen können. Das zweite Kandidatengen G72 DAOA /G30 war durch positive Kopplungsbefunde des chromosomalen Locus für die bipolare Störung und schizophrenen Psychosen identifiziert worden. Neuere Befunde lassen einen Einfluss auf das glutamaterge Transmittersystem vermuten (Chumakov et al. 2002). Das Genprodukt von G72, D-Amino-Oxidase (DAOA) fördert die Oxidation von D-Serine durch D-Amino-Oxidase (DAO), was zum Beinamen D-Amino-Oxidase-Aktivator (DAOA) führte. Da D-Serin ein wichtiger Aktivator des NMDA Glutamatrezeptors ist, könnte G72/DAOA einen wichtigen Faktor für die glutamatergen Signaltransduktion darstellen. Mehrfach wurde eine Assoziation von 69 Markern im Locus G72/G30 mit der bipolaren Depression aber auch schizophrenen Psychosen beschrieben (Detera-Wadleigh et al. 2006). In der Studie sollte eine mögliche Assoziation von SNPs in G72/G30 mit der Erkrankung überprüft und die vorbeschriebenen LD-Blöcke am 5Ende von G72 näher untersucht werden. Dafür wurden sieben SNPs, die sich über den chromosomalen Locus von G72/G30 verteilen, bei 429 Fällen mit affektiven und zykloiden Psychosen und 188 Kontrollen, untersucht. Durch die LD-Analyse der untersuchten SNPs konnte die Ausdehnung der vorbeschriebenen LD-Blöcke in G72 genauer definiert und rs9558575 dem 1. Block zugeordnet werden, der somit bis zum 5-Ende vom G72 reicht. Der SNP rs9558575 am 5- Ende vom G72 wurde erstmalig in dieser Studie untersucht. Trotz adäquater Power (80% bei α = 0,05) erreichte kein Einzelmarker Signifikanzniveau (Tabelle 17). Dennoch zeigten sich Hinweise für eine Beteiligung von G72/G30 am Erkrankungsrisiko, insbesondere für den SNP rs2391191 bei den zykloiden Psychosen. Darüber hinaus scheint der Risikohaplotyp rs2391191A / rs3916966C sowohl für die zykloiden Psychosen (p = 0,002), als auch für die Gesamtgruppe der Affektpsychosen (p = 0,017) ein geeigneter biologischer Marker zu sein. Die in der vorliegenden Studie gefundene Assoziation mit zykloiden Psychosen könnte dabei helfen, die Vorbefunde für G72/G30 als Risikogen sowohl für die bipolare Depression als auch schizophrenen Psychosen zu erklären, da die zykloiden Psychosen nach IDC10 beiden Krankheitsentitäten zugerechnet werden können
In this dissertation two susceptibility genes, FKPP5 and G72/DAOA for the manic depression and monopolar depression were examined by genotyping several single nucleotide polymorphisms (SNPs). In summary, our data do not support a significant genetic contribution of FKBP5 or G72/DAOA to the pathogenesis of affective psychosis in the analysed markers; they may play a role as a disease modificatory factors. FKBP5: A dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been proposed as an important pathogenic factor in depression. Genetic variants of FKBP5, a protein of the HPA system modulating the glucocorticoid receptor, have been reported to be genetically associated with improved response to medical treatment and an increase of depressive episodes. We examined three single nucleotide polymorphisms (SNPs) in FKBP5, rs4713916 in the proposed promoter region, rs1360780 in the second intron and rs3800373 in the 3’-untranslated region (3’-UTR), in a case-control study of Caucasian origin (affective psychosis: n= 248; controls: n= 188) for genetic association and association with disease related traits. Allele and genotype frequencies of rs4713916, rs1360780 and rs3800373 were not significantly different between cases and controls. Odds ratios were not increased between cases and controls, except the rare haplotype G-C-G (OR 6.81), representing 2.1% of cases and 0.3% of controls. The frequency of rs4713916AG in patients deviated from expected Hardy-Weinberg equilibrium, the genotype AA at rs4713916 in monopolar depression (P= 0.011), and the two-locus haplotype rs1360780T - rs3800373T in the total sample (overall P= 0.045) were associated with short duration of disease. In summary, our data do not support a significant genetic contribution of FKBP5 to affective psychosis in the analysed markers, and the findings are inconclusive regarding putative risk haplotypes or association with disease-related traits. G72/DAOA: The chromosomal region 13q32-33 has been found to be linked with bipolar disorder and schizophrenia in several studies. After the description of two genes, G72 and G30, in this region by Chumakov et al 2002, association studies revealed evidence for an association of SNPs at G72/G30 with bipolar disorder, but the results remained heterogeneous with differing risk alleles and missing replication. We examined seven single nucleotide polymorphisms (SNPs) around G7/G30: rs3916966, rs1935058, rs2391191, rs1935062, rs947267, rs3918342, rs9558575, in a case-control study of Caucasian origin (affective psychosis: n= 248; controls: n= 188) for genetic association. Allele and genotype frequencies were not significantly different between cases and controls, no single marker reached statistical significance. We found different specific marker combinations associated with manic depression rs1935062, rs2391191, rs3916966 (overall P=0.022 and monopolar affective disorder, rs1935058, rs947267, rs2391191, rs3916966, rs9558575 (overall P= 0.036), but no well-defined risk haplotype. Our data revealed no clear-cut association with polymorphisms and haplotypes in G72 with disease and did not support a significant genetic contribution of G72 to the pathogenesis of affective psychosis

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36

(7011482), Boning Zhang. "DESIGN OF A PRIVATE PASSAGEWAY FUSION RECEPTOR FOR SENSITIVE CONTROL OF ADOPTIVE CELL THERAPIES." Thesis, 2020.

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Most Adoptive Cell Therapies (ACT), including CAR T cell therapies, suffer failure because of the severe side effects due to loss-of-control of the therapeutic cells once they are inside the patient’s body, suggesting that novel strategies must be developed for a better in vivo control of these engineered cells. In the meantime, CAR T cell therapies targeting solid tumors have not experienced the remarkable success achieved with hematopoietic cancers, mainly due to continuous tumor antigen exposure and a suppressive tumor microenvironment. Here we designed a private passageway fusion receptor, which is composed of a ligand binding domain and a glycosylphosphatidylinositol (GPI) anchoring domain, to be expressed and localized to the surface of CAR T cells independently to the classical CAR T construct. These ligand binding domains preserve high binding affinity towards their cognate ligands and are only expressed on the CAR T cells that have been transduced. Therefore, cytotoxic drugs or immunosuppressants linked to the corresponding targeting ligands are shown to be specifically delivered to these fusion receptor positive CAR T cells for lowering the activity of the over-activated CAR T cells. On the other hand, we discovered that a potent TLR7 agonist is able to enhance the lysis effect of the exhausted CAR T cells in a co-culture model. Serial releasable and non-releasable targeted TLR7 agonists were prepared and tested. Based on these data, we suggest that our secret passageway fusion receptor platform provides a better control of the activity of CAR T cells using the corresponding targeting ligand-payload conjugates in a dose dependent manner and function as a doorway for the delivery of instructions to CAR T cells for versatile purposes.

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37

Gawlik, Micha [Verfasser]. "Assoziations- und Haplotypuntersuchung der Kandidatengene DAOA und FKBP5 bei Patienten mit manisch-depressiver Erkrankung, mit monopolarer Depression oder zykloider Psychose / vorgelegt von Micha Gawlik." 2007. http://d-nb.info/985196866/34.

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Hellenkamp, Kristian. "Einfluss der Calstabin2-Mutante FKBP12.6D37S in gesunden Mauskardiomyozyten und in einem transgenen Herzinsuffizienzmodell, das die Kalzium/Calmodulin-abhängige Proteinkinase IIδc überexprimiert". Doctoral thesis, 2011. http://hdl.handle.net/11858/00-1735-0000-0006-B223-A.

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Di, Sante Jessica. "Méthylation de gènes liés au stress à travers différents tissus périphériques humains, et la pertinence pour le fonctionnement cérébral." Thèse, 2017. http://hdl.handle.net/1866/19431.

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