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1
Lastivka, I. V. "Clinical case of tuberous sclerosis." Thesis, БДМУ, 2022. http://dspace.bsmu.edu.ua:8080/xmlui/handle/123456789/19769.
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O'Callaghan, Finbar J. K. "Tuberous sclerosis : a population based study." Thesis, University of Bath, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.392018.
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McCartney, Deborah Lynn. "Spatial cognition in tuberous sclerosis complex." Thesis, University of Cambridge, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.611280.
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Shepherd, Charles William. "A clinical evaluation of tuberous sclerosis complex." Thesis, Queen's University Belfast, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.282044.
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Ridler, Khanum. "Neuroimaging and neuropsychology in tuberous sclerosis complex." Thesis, University of Cambridge, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.616471.
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De, Vries Petrus Johannes. "The psychopathologies of attention in tuberous sclerosis." Thesis, University of Cambridge, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.620296.
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Mahmood, Ali Abdullah. "MOLECULAR GENETIC ANALYSIS OF THE TUBEROUS SCLEROSIS COMPLEX." Thesis, Indian Institute of Science, 2004. http://hdl.handle.net/2005/73.
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Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that affects several organs in the human body including the brain, heart, kidneys, eyes, skin, spleen, liver and lungs [Roach, et al., 1999]. TSC is characterized by hamartomas that rarely progress to malignancy in the affected organs. Clinical symptoms of TSC include cortical tubers and subependymal nodules in the brain, seizures, mental retardation, ungual and periungual fibromas, angiofibromas of the face, and angiomyolipomas in the kidneys [Roach, et al., 1999]. TSC displays genetic heterogeneity with two known loci: TSC1 on chromosome 9q34 [Fryer, et al., 1987a] and TSC2 on chromosome 16p13.3 [Kandt, et al., 1992]. The genes for both loci have been isolated and characterized [ The European Chromosome 16 Tuberous Sclerosis Consortium, 1993; van Slegtenhorst, et al., 1997].
The TSC1 gene contains 21 coding and two non-coding exons and encodes for an 8.6 kb mRNA. It spans 45 kb of genomic DNA and codes for hamartin, a 1,164 amino acid protein of 130 kDa. The TSC2 encodes for a 200 kDa protein, tuberin, and spans 43 kb of genomic DNA. The TSC2 gene consists of 41 coding exons and one non-coding exon and encodes for a 5.4 kb mRNA. Both genes are known to function as tumor suppressors [Carbonara, et al., 1994; Green, et al., 1994a; Green, et al., 1994b].
Several groups have performed mutation analysis of both the genes in patients mainly from the western and Japanese populations. A total of 133 mutations in the TSC1 gene and 350 mutations in the TSC2 gene have been reported so far (Human Gene Mutation Database; http://archive.uwcm.ac.uk/uwcm/mg/hgmd0.html). However, there is no report on the mutation analysis of the TSC genes from the Indian population. In this study, a total of 24 TSC cases were ascertained from the Indian population and a comprehensive mutation analysis of both the TSC genes was carried out in them to understand the function of both the genes, to locate important domains and also to find the mutational hotspots for molecular diagnosis of TSC. A total of 12 mutations, including seven novel mutations were identified. It was also shown that the most recurrent mutations (c.1831C>T and c.1832G>A) are, in part, due to methylation of the CpG dinucleotide.
There are still 15-25% TSC cases in western populations with undetected mutations [Cheadle, et al., 2000a]. Further, there are familial TSC cases linked either to the TSC1 on 9q34 or TSC2 on 16p13.3 which fail to show any mutations in the coding sequences of both genes [Cheadle, et al., 2000a]. The failure to detect mutations in these cases could be due to several reasons. First, it could be that the mutations lie in the regulatory regions (promoters and enhancers) of both the genes, presently unidentified for the TSC1 gene [Cheadle, et al., 2000a]. Second, it is possible that the mutations lie outside of the coding sequences, within intronic sequences, or in the 5’ or 3’ UTRs [Cheadle, et al., 2000a]. Third, it may be due to the limitation of the techniques used to identify mutations [Cheadle, et al., 2000a]. In order to look for mutations in the promoter, the TSC1 gene promoter was characterized using luciferase reporter gene transfection assay. The promoter for the TSC2 gene is known [Kobayashi, et al., 1997]. The promoters of both TSC1 and TSC2 genes were sequenced in all the 24 cases to look for mutations. During the characterization of the TSC1 gene promoter, a novel isoform involving the non-coding exon 1 of the TSC1 gene was discovered serendipitously.
8
Verhoef, Senno. "Clinical and molecular genetics of tuberous sclerosis complex." [S.l.] : Rotterdam : [The Author] ; Erasmus University [Host], 2001. http://hdl.handle.net/1765/12098.
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Henderson, Keiran Joseph. "Glycosaminoglycans of skin fibroblasts from tuberous sclerosis patients." Thesis, University of Nottingham, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.305187.
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Slegtenhorst, Marjon Annette van. "Tuberous sclerosis complex 1 gene identification and characterisation /." [S.l.] : Rotterdam : [The Author] ; Erasmus University [Host], 1998. http://hdl.handle.net/1765/13665.
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Hancock, Eleanor. "Tuberous sclerosis : clinical factors in long term outcome." Thesis, University of Bath, 2003. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.269678.
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Tuberous sclerosis (TSC) is a dominantly inherited disorder with a high spontaneous mutation rate and a birth incidence of 1 in 10,000. It is a systemic disorder characterised by the growth of hamartomas, which in turn give rise to the clinical manifestations, for example, epilepsy and learning difficulties. Although some patients with TSC are only mildly affected and lead a normal life with typical life expectancy, there is an immense amount of morbidity associated with this disease. In addition, for the majority of patients there is reduced life expectancy. The purpose of this thesis is to look at the clinical factors that contribute to the morbidity and mortality seen in TSC and examine means of reducing the impact of these factors on long-term outcome. It reports a longitudinal population study of a small but defined group of patients looking at the epidemiology and natural history (the morbidity and mortality) suffered by in this population. It investigates the current treatment regimes for the types of epilepsy (infantile spasms and nonconvulsive status epilepticus) known to be associated with the highest risk of learning difficulties in order to determine the most efficacious treatment for the seizures potentially reducing long-term psychomotor delay. A cochrane review of the treatment of infantile spasms was performed. This thesis also examines the effect of exogenous melatonin on sleep disorders (one of the major causes of morbidity) in tuberous sclerosis and the natural circadian rhythms in patients with sleep disorder in TSC and compares them with the normal population. Two important causes of premature mortality in TSC patients are respiratory and renal failure. This thesis examines the prevalence and underlying causes of end stage renal failure in adults with TSC and reviews the literature of LAM (in patients both with and without TSC) investigating further the natural history and treatment of LAM in TSC.
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Janssen, Lambertus Antonius Jacobus. "Locus heterogeneity and the molecular basis of tuberous sclerosis." [S.l.] : Rotterdam : [The Author] ; Erasmus University [Host], 1995. http://hdl.handle.net/1765/12098.
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Uysal, Hamdi. "Extracellular matrix glycoproteins of skin fibroblasts in tuberous sclerosis." Thesis, University of Nottingham, 1995. http://eprints.nottingham.ac.uk/13094/.
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The first main objective of this project was to isolate cellular fibronectin from cultures of skin fibroblasts derived from tuberous sclerosis (TS) patients and normals and to compare their structures, paying particular attention to the content and pattern of carbohydrate (glycosylation). The second main objective of this project was to establish the expression and localisation of glycoproteins fibronectin, laminin and tenascin of the extracellular matrix (ECM) in cultures of skin fibroblasts derived from patients with TS and normal individuals. In order to achieve these objectives, fibroblasts were established from primary cultures of skin explants of patients with TS. Control cells were cultured from skin explants donated by people not known to be suffering from any disorder. The purification of cellular fibronectin was achieved from conditioned medium of skin fibroblasts of TS patients and control fibroblasts using Prosep-gelatin affinity chromatography and gel filtration chromatography techniques. Analysis of purified cellular fibronectin by high pH anion-exchange chromatography with pulsed amperometric detection (HPAEC-PAD) revealed that the carbohydrate portion of the fibronectin molecule was made up of galactose, mannose, glucosamine, galactosamine, sialic acid and fucose. An increased concentration of sialic acid, galactosamine, glucosamine, galactose and mannose was observed in purified fibronectin derived from neck and ungual fibromas of patients with TS. To provide a total increase of carbohydrates more than two fold in comparison to normal fibroblastsderived fibronectin. Purified cellular fibronectin from conditioned medium of fibroblasts grown from skin lesions of different TS patients and from normal skin fibroblasts did not express HNK-1 (anti-leu 7) carbohydrate epitope. Normal skin fibroblasts showed an altered morphology and less confluence when grown on cell culture plates coated with cellular fibronectin derived from TS fibroblasts compared with control fibronectin. This may be a consequence of an altered glycosylation of this protein. The amino acid composition of the purified fibronectin from TS fibroblasts was very similar to that purified fibronectins from normal fibroblasts and to standard commercial plasma and cellular fibronectins. Laminin and tenascin were partially purified from conditioned cell culture medium demonstrating their synthesis and secretion into the cell culture medium by dermal skin fibroblasts. Expression and distribution of fibronectin, tenascin and laminin by established TS and normal skin fibroblasts using immunofluorescence, ELISA, and flow cytometry techniques were analysed and presented qualitative and quantitatively in this thesis. Increased expression and altered distribution of fibronectin and tenascin were observed in the fibroblasts derived from ungual fibroma lesion of a TS patient, but not in fibroblasts of neck fibroma, forehead plaque lesion or unaffacted skin of TS patients in comparison to control fibroblasts. However, increased expression and altered distribution of laminin were observed in neck fibroma-derived fibroblasts in contrast to fibronectin and tenascin. Laminin expression was not changed in ungual fibroma and forehead plaque lesion-derived fibroblasts in comparison to control fibroblasts. Altered distribution of fibronectin was well observed by immunofluorescence particularly in large cells of ungual fibroma. Similar differences were observed with laminin of cells from neck fibroma of TS patients. These results suggest the abnormal assembly of ECM in different TS skin lesions. Abnormal migration of cells during early embryonic development and the hardening of tissues associated with TS may result from abnormal assembly of the ECM. Alterations in distribution and structure of these adhesive glycoproteins may cause functional disruption in their binding and interactions with cells and ECM macromolecules. Studies of these changes in the ECM components may contribute to the understanding of the mechanisms involved in the aetiology of hardened tissues of TS.
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Picker, S. R. "Molecular characterisation of focal cortical dysplasia and tuberous sclerosis." Thesis, University College London (University of London), 2014. http://discovery.ucl.ac.uk/1449523/.
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Introduction: This project focuses on the biological characterisation of 4 important structural causes of severe childhood epilepsy: Focal Cortical Dysplasia (FCD) Type IIb and IIa, and two brain lesions present in Tuberous Sclerosis: cortical tubers and subependymal giant cell astrocytoma (SEGA) tumours. Within these lesions several abnormal cell populations are present, including: Balloon cells, Dysmorphic neurons and SEGA cells. These may represent an aberrant neural progenitor/stem cell population. This raises the hypothesis that a pathological stem cell contributes to the pathogenesis of these diseases. The aim of this study is to identify molecular networks responsible and/or implicated within these lesions. Methods: Differentially expressed genes/exons and microRNAs were identified using the Affymetrix human exon ST1 microarray and NanoString platform respectively. This was performed across the FCD subtypes, cortical tubers, SEGAs and normally formed cortex. WGCNA and IPA network analyses were then applied. Selected proteins based on these results, were validated and investigated by immunohistochemistry of surgical material. Results: Hierarchal clustering of the gene expression between samples was able to reclassify the diseases based on the transcriptome rather than diagnostic subtype. Following a systems biology approach, novel functional networks were identified. A micro-network of: Tenascin C, Palladin, Chitinase-3-like 1, and paired-related-homeobox 1 within the FCD IIb lesion was validated at the protein level, with extracellular-signal-regulated kinase (ERK) as its hub. Additionally, a highly robust subset of alternatively spliced exons specific to the BC harbouring samples were identified. 75.9% of genes identified as differentially expressed between FCD IIa and FCD IIb, were potentially explicable due to the microRNA dysregulation identified. Conclusion: This is the first published gene, exon and microRNA high-throughput analysis performed concurrently for FCD IIb, FCD IIa, cortical tubers and SEGA tumours and the first use of network analysis in these diseases, potentially leading to new therapeutic targets.
15
Woodward, Karen Jane. "Characterisation of the TSCI candidate region on human chromosome 9q34." Thesis, University College London (University of London), 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.283661.
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Gillett, Godfrey Tregelles. "Use of irradiation hybrids in gene mapping on human chromosome II." Thesis, University College London (University of London), 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.322187.
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Millward, Claire. "Neuropsychological functioning in individuals with tuberous sclerosis complex and autism." Thesis, University of East Anglia, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.405403.
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Jeganathan, Dharini. "Identification and analysis of mutations in the TSC1 gene." Thesis, University College London (University of London), 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.326099.
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Yoon, Hae-seong. "A role for the tuberous sclerosis-2 tumor suppressor gene in quinol-thioether-induced nephrocarcinogenicity in the Eker rat /." Full text (PDF) from UMI/Dissertation Abstracts International, 2000. http://wwwlib.umi.com/cr/utexas/fullcit?p3004407.
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Young, David Matthew. "Altered ultrasonic vocalizations in a tuberous sclerosis mouse model of autism." Diss., Search in ProQuest Dissertations & Theses. UC Only, 2010. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3398891.
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Zhou, Chun Yan. "Molecular genetic analysis of the tuberous sclerosis region on chromosome 9." Thesis, University of Cambridge, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.361760.
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Lewis, William. "Changes in Language Pathways in Tuberous Sclerosis Complex Patients with Autism." Thesis, Harvard University, 2014. http://etds.lib.harvard.edu/hms/admin/view/45.
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Tuberous sclerosis complex (TSC) is an autosomal-dominant neurocutaneous disease caused by loss of the TSC1 (encoding hamartin) or TSC2 (encoding tuberin) genes. Neurologic symptoms are common and varied in TSC and include epilepsy and behavioral conditions like autism spectrum disorders (ASD). Between 17 and 61% of children with TSC exhibit symptoms of ASD.
The purpose of this study was to investigate a potential correlate of poor neurological outcome in TSC by assessing the integrity of brain language pathways and the relationship to ASD.
42 patients with TSC and 42 age-matched control subjects were scanned with advanced diffusion-weighted MRI. White matter language pathways were identified with a validated automatic method and analyzed for microstructural characteristics, including fractional anisotropy (FA) and mean diffusivity (MD). Well-defined white matter pathways in the brain are characterized by high FA and low MD. During normal development, brain white matter pathways increase in FA and decrease in MD.
Out of 42 patients with TSC, 12 had ASD (29%). After controlling for age, TSC patients without ASD showed a small decrease in FA of the arcuate fasciculus compared to control subjects, and TSC patients with ASD had much lower FA than both control subjects and TSC patients without ASD. Similarly, while TSC patients without ASD had only a small increase in MD compared to control subjects in the arcuate fasciculus, TSC patients with ASD had much higher MD than control subjects and TSC patients without ASD.
A new method for assessing the microstructure of young patients showed similar results with decreased compactness in language pathways of TSC patients with ASD. Another new method designed to better analyze regions with crossing pathways showed modifications in language pathway microstructure that correlated with ASD diagnosis in the TSC patients. Preliminary analysis of neuropsychiatric data also showed a trend toward an association of arcuate fasciculus MD with verbal IQ, although the result was not significant after multiple comparisons correction.
It remains unclear why some patients with TSC develop ASD, while others have better language outcomes. Our results suggest that aberrant development of language pathways may act as a marker for poor neurological outcome in TSC patients. The impaired microstructure in language pathways of TSC patients may be responsible for the development of ASD, although prospective studies examining the development of language pathways and subsequent ASD diagnosis in this patient population remain essential. It is also possible that a primary problem with language leads to decreased use and subsequent poor development of language pathways. Early diagnosis of ASD is crucial for improving the outcomes of affected children.
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Delaney, Sean Phillip. "Modeling and Therapeutic Development for the Tuberous Sclerosis Related Neoplasm Lymphangioleiomyomatosis." Thesis, Université d'Ottawa / University of Ottawa, 2019. http://hdl.handle.net/10393/39810.
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The multisystemic tumors characteristic of the monogenic neoplastic diseases, tuberous sclerosis complex (TSC) and lymphangioleiomyomatosis (LAM), share common signaling aberrations upon the loss of heterozygosity in either the TSC1 or TSC2 genes. However, their physical manifestations are vastly different and can generally be classified as being either neurological (TSC) or mesenchymal (TSC & LAM; referred to herein as LAM for simplicity) in origin. In this study, I present a comprehensive stem cell model of LAM utilizing multiple TSC2 knockout (TSC2-/-) pluripotent stem cell lines differentiated to the putative cell of origin for mesenchymal tumors, neural crest cells (NCCs). TSC2-/- NCCs faithfully recapitulate LAM phenotypes and temporal RNA-seq analysis of neural and neural crest differentiation was performed to model disease pathogenesis. Analysis revealed immediate activation of stress response signaling resulting in protein aggregation and lysosome and autophagosome accumulation upon neuralization in TSC2-/- cells. This resulted in acute and lasting effects specific to neural progenitor cells (NPCs), that are transient and ameliorated in NCCs. These lineage-specific effects resulted in selective sensitization of NPCs to cell death via proteasome inhibition, suggesting a potential therapeutic avenue for neurological TSC, but not LAM. Thus, a genome-wide CRISPR knockout screen was performed in TSC2-/- NCCs. Analysis of synthetic lethal genes reveals pathways previously targeted for LAM, but provides gene-level resolution to the vulnerable nodes within these pathways. Importantly, 18 novel gene targets were identified that display synthetic lethality to TSC2-/- cells with high specificity. 3 genes within this list were targetable using commercially available small molecule inhibitors, one of which, FGFR1, shows highly selective lethal targeting of TSC2-/- NCCs. Importantly, this model system, paired with the expansive resource of transcriptomic and synthetic lethal data, serves as a foundation for the development of next generation treatment strategies for LAM, and potentially the entire spectrum of TSC manifestations.
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Davies, David Mark. "mTOR inhibition as a therapeutic strategy in tuberous sclerosis or sporadic lymphangioleiomyomatosis." Thesis, Cardiff University, 2011. http://orca.cf.ac.uk/54431/.
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Tuberous sclerosis is an autosomal dominant multisystem disorder characterised by the development of benign tumours in many organs, including the brain, skin, kidneys and heart, seizures and intellectual disability. The condition results from mutations in either of two genes, TSC1 (encoding TSC1) or TSC2 (encoding TSC2). Loss of functional TSC1 or TSC2 leads to activation of mTORCl (mammalian target of rapamycin complex 1), a key regulator of multiple cellular processes including cell growth and division. Lymphangioleiomyomatosis (LAM) is a lung disorder which can lead to respiratory failure and is characterised by the proliferation of abnormal 'LAM' cells LAM occurs in patients with tuberous sclerosis and can also occur as a sporadic disorder due to acquired mutations in TSC2. Renal angiomyolipomas are benign tumours which affects80% of patients with tuberous sclerosis and 40% of patients with sporadic LAM. Sirolimus is an inhibitor of mTORCl and is used in clinical practice as an immunosuppressant. Preclinical studies suggest that TSC1 or TSC2 deficiency renders cells sensitive to mTOR inhibition. This thesis describes a phase 2 trial to assess the safety and efficacy of 2 years of treatment with sirolimus for renal angiomyolipomas in patients with tuberous sclerosis or LAM. Response of angiomyolipoma was the primary efficacy end point. Effects of sirolimus on lung function and neurocognitive function are also reported. Our data show an angiomyolipoma response rate, by RECIST criteria, of 50% in the intention to treat population. There was little change in lung function. Recall but not recognition memory tended to improve. Adverse events were common and consistent with the known toxicities of sirolimus. Our findings suggest that mTOR inhibition is a potential therapeutic strategy in the treatment of tuberous sclerosis and lymphangioleiomyomatosis.
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Bonnet, Cleo S. "Investigating the mechanism of renal cystogenesis in tuberous sclerosis and polycystic kidney disease." Thesis, Cardiff University, 2009. http://orca.cf.ac.uk/55833/.
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Tuberous sclerosis (TSC) is an autosomal dominant disorder caused by germline mutations in either TSC1 or TSC2 and characterised by the development of benign hamartomatous growths in multiple organs and tissues. Clinical trials are underway for the treatment of TSC-associated tumours using mammalian target of rapamycin (mTOR) inhibitors. Here, we show that many of the earliest renal lesions from Tsc1+/ and Tsc2+/ mice do not exhibit mTOR activation, suggesting that pharmacological targeting of an alternative pathway may be necessary to prevent tumour formation. Patients with TSC often develop renal cysts and those with inherited co- deletions of the autosomal dominant polycystic kidney disease (ADPKD) 1 gene (PKD1) develop severe, early onset, polycystic kidneys. Using mouse models, we crossed Tsc1+, and Tsc2+I mice with Pkd1+/ mice to generate double heterozygotes. We found that Tsc1+lPkd1+, and Tsc2+l Pkd1+, mice had significantly more renal lesions than their corresponding single heterozygote littermates indicating a genetic interaction between Tsd and Tsc2 with Pkd1. In agreement with our findings from Tsc1+/ and Tsc2+/ mice, we found that a large proportion of cysts from Tsc1+l Pkd1+, and Tsc2+l Pkd1+, mice failed to stain for pS6, suggesting that initiation of renal cystogenesis in these animals may occur independently of mTOR activation. We analysed primary cilia in phenotypically normal renal tubule epithelial cells by scanning electron microscopy (SEM) and found that those from Tsc1+, and Tsc2+I mice were significantly shorter than those from wild-type littermates (2.122pm and 2.016pm vs. 2.233pm, respectively, P<0.001). Primary cilia from epithelial cells lining renal cysts of Tsc1+' and Tsc2+I' mice were consistently longer (5.157pm and 5.091pm respectively). Interestingly, we found that Pkd1- deficiency coupled with either Tsd or 7sc2-deficiency altered the length of the primary cilia from both normal renal tubule cells (restored to 'wild-type' length) and epithelial cells lining cysts (Tsc1+tPkd1+, Mean 3.38pm and Tsc2+,Pkd1+l Mean 3.09pm). These novel data demonstrate that the Tsc and Pkd1 gene products help regulate primary cilia length which may prevent renal cystogenesis. Consistent with the observation that primary cilia modulate the planar cell polarity (POP) pathway, we found that many dividing pre-cystic renal tubule epithelial cells from Tsc1+/ , Tsc2+/ and Pkd1+/ mice were highly misorientated along the tubule axis. This could potentially lead to tubule dilation and subsequent cyst formation. We therefore propose that defects in cell polarity underlie both TSC and ADPKD-associated renal cystic disease and targeting of this pathway may be of key therapeutic benefit.
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Коленко, Оксана Іванівна, Оксана Ивановна Коленко, Oksana Ivanivna Kolenko, and А. И. Колисниченко. "Туберозный склероз в молодом возрасте." Thesis, Издательство СумГУ, 2003. http://essuir.sumdu.edu.ua/handle/123456789/9255.
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Samia, Pauline Wangechi. "Characteristics of tuberous sclerosis complex in a South African cohort : description and parental understanding." Master's thesis, University of Cape Town, 2009. http://hdl.handle.net/11427/14395.
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Includes bibliographical references (leaves 63-70).Tuberous sclerosis complex (TSC) is a genetically inherited condition that manifests with benign non-invasive tumours or hamartomas in multiple organ systems. The condition is of autosomal dominant inheritance with an estimated incidence of 1 in 6000 live births. Population based studies estimate the prevalence of TSC to be 1 per 14, 492 population. TSC has myriad presentations but 80 to 90% of these children have seizure disorders. The prevalence of learning disabilities in children with TSC ranges from 38% to 80%. Pervasive developmental disorders (PDD) and attention deficit hyperactivity disorder have been identified in half of the children with TSC. Cutaneous manifestations occur in more than 90% of TSC patients. Cortical tubers, cardiac rhabdomyomas and renal angiomyolipomas are other lesions associated with TSC in children. Currently TSC has no cure and associated complications manifest with advancing age. Parents are faced with the challenge of life long care for these children. Half of the parents of children with TSC suffer significant psychological stress. Child specific factors, health literacy, and social stability are some factors known to impact on parental understanding of a child's chronic illness. Data specific to parental understanding of TSC are limited. Methodology: A retrospective case note review was performed to obtain the patient demographic and clinical presentation data. A prospective observational study provided the parental background characteristics and information on their understanding of TSC. Results: A total of 31 patient case notes were included in the review. The median patient age at the time of data was 132 months (IQR 96.00). The male: female ratio was 4:1. Seizures were observed in 27 patients (87.1%). Infantile spasms were reported in 3 (9.6%) patients while partial seizures occurred in 11 (35.5%) patients. More than one anticonvulsant was required in 15 (48.4%) of the 27 patients with seizures. Fourteen (53.8%) had global developmental delay. Two children (6.4%) were both hyperactive and aggressive and six (19.3%) were considered hyperactive. Aggressive behaviour was observed in four (12.9%) other children. Parents of 21 patients gave consent to participate in the study. The median parental age was 38 years (IQR 10.5). Seven parents (33.3%) had attained a primary level of education. Secondary education was attained by ten parents (47.6%) and three (14.3%) had received tertiary education. A statistically significant difference, p value =0.001, was observed in the change in the level of knowledge on comparison between the parent group that received a leaflet and the one that did not. A parental level of education of grade 8 was associated with a significantly higher baseline knowledge score (p value = 0.045) and a significantly greater change in the level of knowledge score (p value = 0.003). No association was detected between a parent's duration of clinic attendance and the baseline level of knowledge (p value = 0.63) There was no association between a parents baseline level of knowledge and their assessment of the impact of TSC on their child. (p value = 0.61). Conclusions and recommendations: The clinical profile of the cohort of children seen at the Red Cross Children's Hospital is similar to that of other cohorts described in literature. Parental understanding of TSC can be improved by provision of written information for those with at least a grade eight level of education. The information leaflet used in this study can be used to educate parents of children with TSC.
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Liang, Ning. "Regulation of YAP by mTOR and autophagy reveals a therapeutic target of Tuberous Sclerosis Complex." Thesis, Paris 5, 2014. http://www.theses.fr/2014PA05T055/document.
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La sclérose tubéreuse complexe (TSC) est une maladie génétique caractérisée par une croissance des hamartomes dans différents organes y compris le cerveau, les reins, les poumons, la peau et le cœur. Ces lésions sont des sources de morbidité et de mortalité chez les patients TSC, car ils peuvent provoquerl’ épilepsie, l’autisme, le retard de développement et l’insuffisance rénale et pulmonaire. Les causes connues de TSC sont la perte de la fonction et les mutations des gènes TSC1 et TSC2. La majorité des lésions TSC contient plusieurs types cellulaires de la lignée mésenchymateuse, comme dans le cas des angiomyolipomes, l’lymphangioleiomyomatose et les angiofibromes. Un type unique de cellules épithélioïdes périvasculaires nommé (PEC) est constamment présent dans les lésions de TSC mésenchymateuses, comme angiomyolipomes et lymphangioleiomyomatose, basant sur les caractérisations morphologiques et l'expression des marqueurs communs mélanocytaires et myogéniques. Par conséquent, ces lésions sont officiellement classées, ainsi que d'autres tumeurs, comme PEComes. Leur origine cellulaire et les mécanismes moléculaires impliqués dans la pathologie restent à élucider. Ici, nous avons généré un modèle souris mosaïque TSC1 knockout qui développe des lésions rénales mésenchymateuses récapitulant périvasculaire épithélioïde cellules tumorales humaines (Pecoma) observés chez les patients TSC. Nous avons identifié YAP, le co-activateur transcriptionnel de la voie Hippo, a été régulée d'une manière mTOR-dépendante dans les lésions rénales de notre TSC1 knockout souris et les échantillons de l’angiomyolipome humaines. L'inhibition de YAP avec des outils génétiques ou pharmacologiques atténue considérablement la prolifération et la survie des cellules nulles TSC1 in vivo et in vitro. En outre, l’accumulation de YAP dans les cellules déficientes TSC1 / TSC2 pourra être dû à la dégradation de la protéine altéré par le système de l’autophagosome / lysosome. Ainsi, la régulation de YAP par mTOR et l'autophagie est un nouveau mécanisme de contrôle de la croissance, l'activité de YAP correspondant à la disponibilité des éléments nutritifs dans les conditions de croissance permissives. Il pourra servir comme une cible thérapeutique potentielle pour TSC et d'autres maladies avec une activité de mTOR déréguléeThe Tuberous Sclerosis Complex (TSC) is a genetic disease characterized by growth of hamartomas in different organs including brain, kidney, lung, skin, and heart. These lesions are sources of morbidity and mortality in patients with TSC, as they may cause intractable epilepsy, autism, developmental delay, renal and pulmonary failure. Known causes of TSC are loss of function mutations in TSC1 and TSC2 genes. The majority of TSC lesions contain multiple cell types of the mesenchymal lineage, as in the case of angiomyolipomas, lymphangioleiomyomatosis and angiofibromas. A unique cell type named perivascular epithelioid cell (PEC) is constantly present in mesenchymal TSC lesions, such as angiomyolipomas and lymphangioleiomyomatosis, basing on morphological features and the common expression of melanocytic and myogenic markers. Therefore, these lesions are officially classified, along with other tumors, as PEComas. Their cell of origin and the molecular mechanisms underlying their pathogenesis remain poorly defined. Here we generated a novel mosaic Tsc1 knockout mouse model which develop renal mesenchymal lesions recapitulating human Perivascular Epithelioid Cell tumor (PEComa) observed in TSC patients. We identified YAP, the transcriptional coactivator of Hippo pathway, was upregulated in both renal lesions of TSC mouse model and human angiomyolipoma samples in a mTOR-dependent manner. Inhibition of YAP with genetic or pharmacological tools greatly attenuates the proliferation and survival of Tsc1 null cells in vivo and in vitro. Futhermore, we found YAP accumulation in TSC1/TSC2 deficient cells is due to impaired degradation of the protein through the autophagosome/lysosome system. Thus the regulation of YAP by mTOR and autophagy is a novel mechanism of growth control, matching YAP activity with nutrient availability under growth permissive conditions. It may serve as a potential therapeutical target for TSC and other diseases with dysregulated mTOR activity
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Kalogerou, Maria. "Targeting the mTOR signalling pathway for prevention and therapy of tuberous sclerosis in mouse models." Thesis, Cardiff University, 2013. http://orca.cf.ac.uk/58407/.
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Tuberous sclerosis is an autosomal dominant genetic disorder characterised by the development of benign tumours in multiple organs. It is caused by mutations in the TSC1 or TSC2 tumour suppressor gene, leading to hyperactivation of mTOR signalling in affected tissues. Rapamycin and its analogues are mTOR inhibitors and have been used to treat tuberous sclerosis in both pre-clinical and clinical trials. However, tumours usually relapse after drug withdrawal. The aims of this project were to identify novel agents and strategies for prevention and therapy of tuberous sclerosis using mouse models. First T2 weighted MRI was evaluated for assessment of renal lesions in Tsc1+/- and Tsc2+/- mouse models. MRI identified all types of Tsc-associated renal lesions in both Tsc mouse models. The smallest detectable lesions were <0.1 mm3. Eighty five percent of all renal lesions detected in a first scan at 12 months of age were re-identified in a second scan 2 months later. Between the two scans, MRI revealed a significant increase in the total number and volume of lesions in 9 untreated mice. Compared to histological analysis, MRI detected most cysts and papillary tumours (64%) but only a minority of solid tumours (30%). Metformin is a mild inhibitor of mTOR. The therapeutic effect of metformin on renal lesions in Tsc1+/- mice was investigated using T2 weighted MRI and histological analysis. Metformin treatment for 9 months had no significant effect on renal lesions in these mice. Finally, the preventive effects on renal lesions in Tsc2+/- mice of rapamycin, metformin or both agents in combination were assessed using histological analysis. Treatment started from one month of age and continued for 7 to 9 months. Rapamycin or rapamycin plus metformin but not metformin alone effectively blocked the development of renal lesions including cysts, adenomas and carcinomas through the inhibition of mTOR signalling. These findings suggest that mTOR inhibition may be an effective strategy for preventing emergence of disease manifestations in tuberous sclerosis.
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Lu, Yiyang. "Exploring Rapamycin-induced Pro-survival Pathways in Tuberous Sclerosis Complex and the Development of Alternative Therapies." University of Cincinnati / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1613752713277464.
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Chidi, Mehdi [Verfasser], and Karsten Henning [Akademischer Betreuer] Wrede. "Intracranial aneurysms in patients with tuberous sclerosis complex: a systematic review / Mehdi Chihi ; Betreuer: Karsten Henning Wrede." Duisburg, 2020. http://d-nb.info/1212362667/34.
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Leclezio, Loren. "Pilot validation of the Tuberous Sclerosis Associated Neuropsychiatric Disorders (TAND) checklist as a screening tool for neuropsychiatric manifestations." Master's thesis, University of Cape Town, 2014. http://hdl.handle.net/11427/5934.
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Hsieh, Ting-Chiu. "Tuberous sclerosis complex 1 (Tsc1) regulates dE2F1 protein expression during development and cooperates with Rbf1 to control proliferation and survival in «Drosophila melanogaster»." Thesis, McGill University, 2010. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=95246.
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Retinoblastoma tumour suppressor Rb is a cell cycle regulator that is active during early G1 preventing the transition from G1 to S-phase. This is achieved by Rb inhibiting E2F transcription factors from activating expression of genes required for G1 to S-phase progression and DNA synthesis. In our initial genetic test searching for genes that interact with mutations of rbf1, the homologue of rb in Drosophila melanogaster, one of the genes identified was tsc1, which is also a tumour suppressor gene that regulates translation and cell growth. We found that in Drosophila eye imaginal disc cells, tsc1 and rbf1 mutations have a synergistic effect on increasing the level of cell death and promoting ectopic S-phase entry. In addition, I found that dE2F1 protein level increased in tsc1 mutant eye disc cells, which implies that Tsc1 is a negative regulator of dE2F1 expression. The goal of my thesis study was to characterize the synergistic relation between Rbf1 and Tsc1 as well as the regulation of dE2F1 expression by Tsc1. In cells triple-mutant for rbf1, tsc1, and de2f1, I found that the observed elevation in cell death in rbf1 and tsc1double-mutant cells was suppressed, which suggests that the cooperation between Rbf1 and Tsc1 is dE2F1-dependent. Moreover, by using a reporter construct for dE2F1 activity, PCNA-GFP, and performing in situ hybridization with anti-sense RNA probes of dE2F1 target genes, rnrS, Cyclin E, and PCNA, I showed that activities of de2f1 downstream target genes were activated by tsc1 mutations, suggesting that Tsc1 also regulates dE2F1 target gene expression. Through clonal analysis of loss-of-function mutant alleles of the canonical Tsc pathway genes, I found that Tsc1 regulates dE2F1 via the Tsc pathway, specifically tsc/rheb/Tor/s6k. Finally, my RTq-PCR result showed that the regulation of dE2F1 protein expression by Tsc1 is at post-transcriptional level. To address whether the regulation is at the level of translation, I cloned the 5' untranLe suppresseur de tumeur du Rétinoblastome, Rb, est un régulateur du cycle cellulaire qui est actif dans la phase précoce G1, prévenant le passage en phase S. Pour ce faire Rb inhibe le facteur de transcription E2F, l'empêchant d'activer l'expression de gènes requis pour le passage de la phase G1 à la phase S et pour la synthèse d'ADN. Dans nos tests génétiques initiaux, cherchant des gènes interagissant avec la mutation rbf1, l'homologue de rb chez Drosophila Melanogaster, un des gènes identifié fut tsc1, qui est également un gène suppresseur de tumeur qui régule la traduction et la croissance cellulaire. Nous avons découvert que dans les cellules des disques imaginaux des yeux, les mutations tsc1 et rbf1 ont un effet synergique sur l'augmentation du taux de mort cellulaire et promeuvent l'entrée en phase ectopique S. Il fut également découvert que le taux de la protéine dE2f1 augmente dans les cellules mutantes du disque des yeux, ce qui implique que Tsc1 est un régulateur négatif de l'expression de dE2F1. Le but de ma thèse était de caractériser la régulation de l'expression de dE2F1 par Tsc1 et la relation de synergie entre Rbf1 et Tsc1. Dans les cellules triples mutantes pour rbf1, tsc1, et de2f1, j'ai trouvé que l'augmentation du taux de mort cellulaire observé disparaissait dans les cellules doubles mutantes rbf1 et tsc1, ce qui suggère que la coopération entre Rbf1 et Tsc1 est dE2F1-dependante. Egalement, en utilisant un gène rapporteur de l'activité de de2f1, PCNA-GFP, et en réalisant des hybridations in situ avec des sondes ARN anti sens, rnrS, Cyclin E, and PCNA, j'ai montré que l'activité de la région en aval des gènes cibles de de2f1 était activé par la mutation tsc1, suggérant que Tsc1 régule également l'expression des gènes cible de dE2F1. Par l'analyse de clones possédant des allèles mutants perte de fonction pour les gènes de la cascade canonique Tsc, j'ai trouvé que Tsc1 régule dE2F1 par le biais$
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Carlisle, Kathleen Walker. "School Factors Related to the Social and Behavioral Success of Children and Adolescents with Tuberous Sclerosis: Special Education Placement, Services, and Parental Involvement." [Tampa, Fla.] : University of South Florida, 2003. http://purl.fcla.edu/fcla/etd/SFE0000154.
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Alzhrani, Jasser Ali S. "Na+/K+ Pump and Cl--coupled Na+ and K+ co-transporters in Mouse Embryonic Fibroblasts lacking the Tuberous Sclerosis Complex TSC1 and TSC2 genes." Wright State University / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=wright1440683830.
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Hien, Annie. "Regulation of Translation and Synaptic Plasticity by TSC2." eScholarship@UMMS, 2020. https://escholarship.umassmed.edu/gsbs_diss/1097.
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Mutations in TSC2 cause the disorder tuberous sclerosis (TSC), which has a high incidence of autism and intellectual disability. TSC2 regulates mRNA translation required for group 1 metabotropic glutamate receptor-dependent synaptic long-term depression (mGluR-LTD), but the identity of mRNAs responsive to mGluR-LTD signaling in the normal and TSC brain is largely unknown. We generated Tsc2+/- mice to model TSC autism and performed ribosome profiling to identify differentially expressed genes following mGluR-LTD in the normal and Tsc2+/- hippocampus. Ribosome profiling reveals that in Tsc2+/-mice, RNA-binding targets of Fragile X Mental Retardation Protein (FMRP) are increased. In wild-type hippocampus, induction of mGluR-LTD caused rapid changes in the steady state levels of hundreds of mRNAs, many of which are FMRP targets. Moreover, mGluR-LTD signaling failed to promote phosphorylation of eukaryotic elongation factor 2 (eEF2) in Tsc2+/- mice, and chemically mimicking phospho-eEF2 with low cycloheximide enhances mGluR-LTD in the Tsc2+/- brain. These results suggest a molecular basis for bidirectional regulation of synaptic plasticity by TSC2 and FMRP. Furthermore, deficient mGluR-regulated translation elongation contributes to impaired synaptic plasticity in Tsc2+/- mice.
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Gupta, Nishant. "The NHLBI Lymphangioleiomyomatosis (LAM) Registry: Longitudinal Analysis to Determine the Natural History of LAM." University of Cincinnati / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1504879473662385.
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Zügge, Karin Louise. "Molecular genetic investigation of the variability of the GTPase activating protein- (GAP-) related domain of the tuberous sclerosis-2 (TSC2) gene in TSC patients and healthy subjects." [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=972115366.
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Hale, Amber N. "ANALYSIS OF THE ROLE OF TWO AUTOPHAGY PATHWAY RELATED GENES, BECN1 AND TSC1, IN MURINE MAMMARY GLAND DEVELOPMENT AND DIFFERENTIATION." UKnowledge, 2014. http://uknowledge.uky.edu/biology_etds/18.
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The mammary gland is a dynamic organ that undergoes the majority of its development in the postnatal period in four stages; mature virgin, pregnancy, lactation, and involution. Every stage relies on tightly regulated cellular proliferation, programmed cell death, and tissue remodeling mechanisms. Misregulation of autophagy, an intracellular catabolic process to maintain energy stores, has long been associated with mammary tumorigenesis and other pathologies. We hypothesize that appropriate regulation and execution of autophagy are necessary for proper development of the mammary ductal tree and maintenance of the secretory epithelia during late pregnancy and lactation. To test this hypothesis we examined the role of two genes during development of the mammary gland.
Beclin1 (Becn1) is an essential autophagy gene. Since the Becn1 knockout model is embryonic lethal, we have generated a Becn1 conditional knockout (cKO). We used two discrete mammary gland-specific Cre transgenic lines to interrogate the role of BECN1 during development. We report that MMTV-CreD; Becn1fl/fl mice have a hyper-branching phenotype and WAP-Cre; Becn1fl/- mice are unable to sustain a lactation phase. Becn1 mutants exhibit abnormal glandular morphology during pregnancy and after parturition. Moreover, when autophagy is chemically inhibited in vitro, mammary epithelial cells have an increased mean number of lipid droplets per cell.
MTOR inhibits autophagy upstream of BECN1; we looked higher in the regulatory pathway for regulatory candidates. It has been well characterized that Tuberous sclerosis complex 1 (TSC1), in a heterodimer with its primary binding partner TSC2, inhibits MTOR signaling via inhibition of RHEB. Using the Tsc1 floxed model we generated a mammary gland specific Tsc1 cKO and found that these mice phenocopy the Becn1 cKO mice, including a gross lactation failure. Tsc1 cKO glands have altered morphology, retained lipid droplets in secretory epithelia, and an overall increase in MTOR signaling. We show that TSC1 and BECN1 are interacting partners, and that the interaction is nutrient responsive.
These results suggest that Becn1 and Tsc1 are necessary for proper mammary gland development and differentiation. Furthermore, we have demonstrated a novel murine protein-protein interaction and an important link between regulation of MTOR pathway and regulation of autophagy in a developmental context.
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Almeida, Luiz Gustavo Dufner de. "Estudo mutacional em pacientes com o complexo da esclerose tuberosa." Universidade de São Paulo, 2014. http://www.teses.usp.br/teses/disponiveis/41/41131/tde-09122014-085619/.
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O complexo da esclerose tuberosa (TSC) é um transtorno genético, sistêmico, com expressividade variável e herança autossômica dominante. Clinicamente manifesta-se devido ao desenvolvimento de hamartomas e hamártias em diferentes tecidos, principalmente no cérebro, rins, coração, pele e pulmões, podendo causar disfunção do órgão. Mutação em um de dois genes supressores tumorais, TSC1 ou TSC2, são responsáveis pelo TSC. Os genes TSC1 e TSC2 codificam para hamartina e tuberina, respectivamente. Ambas as proteínas interagem fisicamente formando um complexo citosólico que inibe mTOR (mammalian target of rapamycin). Testes moleculares para TSC1 e TSC2 são úteis para auxiliar no diagnóstico de casos clínicos difíceis, em aconselhamento genético e estudos de associação genótipo-fenotípica, além de permitirem a caracterização molecular de mecanismos patogenéticos da formação dos hamartomas e análises funcionais de seus produtos gênicos. Apesar de o diagnóstico de TSC ser basicamente clínico, a partir da revisão de seus critérios em 2012 por um grupo de especialistas, o achado de uma mutação em TSC1 ou TSC2 passou a ser considerado suficiente para o diagnóstico definitivo da doença. O estudo apresentado aqui é parte de um projeto em andamento para estabelecer condições ao desenvolvimento de análise de mutações causadoras de TSC nos genes TSC1 e TSC2. Nosso objetivo neste trabalho foi avaliar por sequenciamento de Sanger o DNA genômico de 28 pacientes brasileiros com diagnóstico definitivo de TSC, procedentes dos estados de São Paulo ou Paraná, tendo como alvo a sequência codificadora do gene TSC1, parte de seus segmentos intrônicos, o promotor basal, bem como o segmento imediatamente a 5\' deste. Sete pacientes (25%) apresentaram mutações de sentido trocado (nonsense) ou com deslocamento da leitura à tradução (frameshift) no gene TSC1. Entre 31 outras variantes de DNA encontradas, 23 são polimorfismos conhecidos e oito apresentaram frequência inferior a 1%, como verificado in silico entre mais de mil sequências de genomas humanos. Entre essas oito variantes de DNA novas ou raras, quatro foram detectadas em pacientes para os quais uma mutação patogênica havia sido identificada e, por isso, foram reclassificadas como polimorfismos. Duas e uma variantes de DNA do mesmo paciente flanqueavam um sítio de ligação em potencial para um fator de transcrição específico, a 5\' do promotor basal de TSC1. Por fim, uma nova variante de DNA na região não codificadora do éxon 2 do gene TSC1 foi predita com potencial para alterar um elemento candidato a acentuador de splicing. Em resumo, como observado em estudos anteriores, descrevemos aqui 25% dos pacientes com TSC apresentando mutações patogênicas na sequência codificadora do gene TSC1. Nossos dados mostraram quatro novas variantes de DNA em regiões potencialmente reguladoras da expressão do gene TSC1, que podem revelar-se como mutações patogênicas e, portanto, necessitam ser testadas experimentalmenteTuberous sclerosis complex (TSC) is a multisystem disorder, with variable expression and autosomal dominant inheritance. Clinically it is due to hamartia and hamartoma development in different tissues, notably in the brain, kidneys, heart, skin and lungs, causing organ dysfunction. Mutations in either tumor suppressor gene, TSC1 or TSC2, are responsible for TSC. TSC1 and TSC2 genes code for hamartin and tuberin, respectively. Both proteins physically interact forming a cytosolic complex that inhibits the mammalian target of rapamycin (mTOR). TSC1 and TSC2 molecular testing has been useful in diagnosing clinically challenging cases, in genetic counseling and genotype/phenotype association studies, besides evaluation of the molecular basis of hamartoma formation and functional analyses of both gene products. Although TSC diagnosis is basically clinical, since the 2012 specialist panel review the finding of a TSC1 or TSC2 mutation has been considered sufficient for the definite diagnosis of the disease. The results presented here are part of an ongoing project to establish conditions for TSC1 and TSC2 mutation studies. Our first aim is to evaluate by Sanger sequencing TSC1 coding sequence, and an average of 132 base pairs of intronic regions next to exon boundaries from TSC patients, in addition to the gene core promoter. We present preliminary results of a sample of 28 patients with definite TSC diagnosis, from São Paulo and Paraná states. Seven patients (25%) displayed TSC1 nonsense or frameshift mutations. Among 31 other DNA variants identified, 23 were known polymorphisms, and eight had frequencies below 1% as verified in silico among more than a thousand human genomes. Out of eight novel or rare DNA variants, four were detected in patients for whom a pathogenic mutation had been found. Two and one additional DNA point variants from the same patient flanked a putative transcription factor binding site. Finally, a novel DNA variant residing in the TSC1 noncoding exon 2 was predicted to change the sequence potential to behave as a splicing enhancer. In summary, similar to previous studies, we describe 25% of TSC patients with mutations in the TSC1 coding sequence. Differently from other reports, our data disclose four novel DNA variants in TSC1 potentially regulatory regions that are likely to unravel novel pathogenic mutations, and thus need to be experimentally tested
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Marín, Alexandra Belén Saona. "Capacidade proliferativa in vitro de precursores neuro-gliais, telencefálicos e expressão dos genes 1 e 2 do Complexo da Esclerose Tuberosa (TSC1 e TSC2)." Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/41/41131/tde-08032013-105224/.
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O complexo da esclerose tuberosa (TSC) é um transtorno clínico, com expressividade variável, caracterizado por hamartomas que podem ocorrer em diferentes órgãos. Tem herança autossômica dominante e é devido a mutações em um de dois genes supressores de tumor, TSC1 ou TSC2. Estes codificam para as proteínas hamartina e tuberina, respectivamente, que se associam formando um complexo macromolecular que regula funções como proliferação, diferenciação, crescimento e migração celular. As lesões cerebrais podem ser muito graves em pacientes com TSC e caracterizam-se por nódulos subependimários (SEN), astrocitomas subependimários de células gigantes (SEGA), tuberosidades corticais e heterotopias neuronais, podendo relacionar-se clinicamente à epilepsia refratária à terapia medicamentosa, deficiência intelectual, desordens do comportamento e hidrocefalia. O potencial de crescimento de SEGA até os 21 anos de idade dos pacientes exige acompanhamento periódico por exame de imagem e condutas clínicas ou cirúrgicas, conforme indicação médica. As lesões subependimárias têm sido explicadas por déficits de controle da proliferação, crescimento e diferenciação de precursores neuro-gliais na zona subventricular telencefálica. Embora a capacidade da tuberina em inibir a proliferação celular pela repressão do alvo da rapamicina em mamíferos (mTOR) esteja bem documentada, outros aspectos celulares do desenvolvimento de SEGA ainda não foram examinados. Assim, é importante estabelecer um sistema in vitro para o estudo de células da zona subventricular e testá-lo na análise das proteínas hamartina e tuberina. Neste sentido, o cultivo de neuroesferas em suspensão é muito apropriado. Neste estudo, buscamos relacionar a expressão e distribuição subcelular da hamartina e tuberina à capacidade proliferativa e de diferenciação das células de neuroesferas cultivadas in vitro a partir da dissociação da vesícula telencefálica de embriões de ratos normais. Analisamos a expressão e distribuição subcelular da hamartina e tuberina por imunofluorescência indireta em células entre a primeira e a quarta passagens das neuroesferas, sincronizadas nas fases G1 ou S do ciclo celular e após a reentrada no ciclo celular, através da incorporação de 5-bromo-2\'-desoxiuridina (BrdU) e imunofluorescência com anticorpo anti-BrdU. Em geral, células de neuroesferas apresentaram baixa colocalização entre hamartina e tuberina in vitro. A expressão da tuberina foi elevada em basicamente todas as células das esferas e fases do ciclo celular; ao contrário, a hamartina apresentou-se principalmente nas células da periferia das esferas. A colocalização entre hamartina e tuberina foi observada em células mais periféricas das esferas, sobretudo no citoplasma e, em G1, no núcleo celular. A proteína rheb, que conhecidamente interage diretamente com a tuberina, apresentou distribuição subcelular muito semelhante à desta. Ao carenciamento das células visando à parada do ciclo celular na transição G1/S, tuberina distribuiu-se ao núcleo celular em quase todas as células avaliadas e, de forma menos frequente, a hamartina também. À reentrada no ciclo celular pelo reacréscimo dos fatores de crescimento, avaliaram-se células com incorporação de BrdU ao seu núcleo celular, após 72 e 96 horas. Nestas, tuberina mostrou-se novamente no citoplasma de forma preponderante e hamartina manteve-se citoplasmática, em geral subjacente à membrana plasmática, em níveis mais baixos. Os grupos cujas células reciclaram por 72 ou 96 horas diferiram quanto ao aumento significativo da expressão da hamartina em células proliferativas no último. À diferenciação neuronal, aumentaram-se os níveis de expressão de hamartina observáveis à imunofluorescência indireta, tornando-se equivalentes àqueles da tuberina. Concluímos que as células de neuroesferas cultivadas em suspensão apresentam-se como um sistema apropriado ao estudo da distribuição das proteínas hamartina e tuberina e sua relação com o ciclo celularThe tuberous sclerosis complex (TSC) is a clinical disorder with variable expressivity, characterized by hamartomas that can occur in different organs. It has autosomal dominant inheritance and is due to mutations in one of two tumor suppressor genes, TSC1 or TSC2. These encode for the proteins hamartin and tuberin, respectively, which are associated in a macromolecular complex which functions as a regulator of cell proliferation, differentiation, growth and migration. TSC brain lesions may be severe and are characterized by subependymal nodules (SEN), subependymal giant cell astrocytomas (SEGA), neuronal heterotopias and cortical tubers, and may be clinically related to refractory epilepsy, intellectual disability, behavioral disorders and hydrocephaly. The growth potential of SEGA up to 21 years of age in TSC patients requires regular monitoring by imaging. Clinical and surgical interventions may be medically indicated. Subependymal lesions have been explained by deficient control of proliferation, growth and differentiation of neuro-glial progenitors from the telencephalic subventricular zone. While tuberin ability to inhibit cell proliferation by repressing the mammalian target of rapamycin (mTOR) has been well documented, other cell aspects of SEGA development have not been thoroughly examined. Therefore, it is important to establish conditions for an in vitro system to study the cells from the subventricular zone and to test its suitability for the study of the TSC proteins. In this regard, the neurosphere suspension culture is very appropriate. We evaluated the expression and subcellular distribution of hamartin and tuberin in relation to the proliferation and differentiation capability of neurosphere cells derived in vitro from the dissociation of the telencephalic vesicle of normal E14 rat embryos. These analyses were performed by indirect immunofluorescence in cells from first through fourth passages of neurospheres, synchronized in G1 or S phases of the cell cycle, and after reentry into the cell cycle by the addition of 5-brome-2\'-desoxyuridine (BrdU) and immunolabeling with anti-BrdU antibody. In general, neurosphere cells presented low colocalization between hamartin and tuberin in vitro. Tuberin expression was relatively high in basically all neurosphere cells and cell cycle phases, whereas hamartin distributed mainly to cells from the periphery of the spheres. In these cells, hamartin and tuberin colocalization was evident mostly in the cytoplasm and, in G1, also in the cell nucleus. Rheb, which is known to interact directly with tuberin, had subcellular distribution very similar to tuberin. Cell starvation indicating cell cycle arrest at G1/S redistributed tuberin to the cell nucleus in virtually all cells examined, what was accompanied by nuclear location of hamartin in a small subset of cells. When cells were allowed to reenter cell cycle by adding growth factors, we evaluated BrdU-labeled nuclei 72 and 96 hours later. In the two groups, tuberin was shown to move back to the cytoplasm as well as hamartin, which apparently maintained its lower expression levels distribution underneath the plasma membrane. Group of cells that recycled for 96 hours had significantly more expression of hamartin than those cells that cycled for only 72 hours. After neuronal differentiation, hamartin expression levels observed by immunofluorescence were similar to those of tuberin. We conclude that neurosphere cells cultured in suspension showed to be an appropriate cell system to study hamartin and tuberin distribution in respect to the cell cycle
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Azzi-Nogueira, Deborah. "Os produtos dos genes Tsc1 e Tsc2 em processos neurodegenerativos." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/41/41131/tde-09122016-154805/.
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O complexo da esclerose tuberosa (TSC) é uma doença genética que pode afetar órgãos específicos de qualquer sistema do organismo humano. Em geral, as lesões surgem pela inativação bialélica de um dos genes supressores tumorais Tuberous Sclerosis Complex 1 (TSC1) ou 2 (TSC2). Por outro lado, nas regiões corticais e subcorticais do cérebro, as lesões decorrentes de falhas de migração neuronal e sua arborização podem ser explicadas pela haploinsuficiência de TSC1 ou TSC2. As lesões do córtex cerebral apresentam-se comumente com epilepsia refratária, a qual, por sua vez, pode se associar a deficiência intelectual e transtornos do comportamento. Estes quadros clínicos podem estar presentes em pacientes com TSC sem lesão anatômica detectável à ressonância nuclear magnética do crânio. As proteínas hamartina ou tuberina, conhecidas também como TSC1 e TSC2, são codificadas respectivamente pelos genes TSC1 e TSC2. Elas agem juntas em um complexo molecular citosólico que inativa a pequena GTPase Rheb, a qual tem ação ativadora da cinase alvo da rapamicina em mamíferos (mTOR), regulando diversos processos celulares, como proliferação, diferenciação, crescimento, migração e metabolismo. Com a hipótese de que a quantidade de TSC1 ou TSC2 no neurônio pode alterar suas funções de forma dependente do estado metabólico, tivemos, neste trabalho, o objetivo geral de caracterizar os padrões de expressão e atividade de TSC1 e TSC2 em dois modelos de neurodegeneração induzida no camundongo adulto e verificar se a redução de quantidade de TSC1 tem efeito sobre a extensão da lesão de neurônios dopaminérgicos em modelo de hemiparkinsonismo. No primeiro modelo empregado, cinco estruturas encefálicas de camundongos submetidos a dieta hiperlipídica mostraram alteração da quantidade de RNAm de Tsc1 e/ou Tsc2 ou sinais de estresse oxidativo. A redução de transcritos de Tsc1 e Tsc2 no córtex cerebral foi dependente de jejum realizado imediatamente antes da eutanásia. No córtex cingulado, houve evidência de estresse oxidativo. O aumento específico de RNAm foi observado no hipocampo (Tsc1 e Tsc2) e no estriado e hipotálamo (Tsc1), embora de forma independente do jejum, sugerindo se tratar de alterações relacionadas à dieta hiperlipídica. No modelo de hemiparkinsonismo, camundongos adultos submetidos a injeção intracerebral de 6-hidroxidopamina apresentaram redução da quantidade total de proteína S6 no lado encefálico tratado quando comparado ao segmento contralateral (p =0,004, r=0,8795; teste de Pearson, IC: 95%), sem alteração de TSC1 ou TSC2. Em análises de imunoperoxidase do encéfalo, descrevemos, de forma independente da lesão, a expressão de TSC1 no estriado, núcleos entopeduncular e arqueado e de TSC2 no tálamo e hipotálamo. Com o objetivo de obter um modelo de camundongo sem expressão pós-natal de Tsc1 em várias regiões encefálicas, de forma independente do tipo celular, realizamos cruzamentos entre uma linhagem de camundongo transgênico em que o gene Tsc1 contém sequências lox nos íntrons 16 e 18 e outra linhagem com Tsc1 tipo-selvagem (WT) em homozigose e o transgene para expressão da recombinase Cre em fusão ao domínio de ligação ao ligante do receptor de estrógeno humano (ESR1) sob o controle de expressão do promotor de ubiquitina C (UBC). Em F1, obtivemos camundongos portadores do transgene UBC-CreESR1 e heterozigotos para Tsc1 (Tsc1WT/Flox). Em F2, entre os animais homozigotos Tsc1Flox/Flox (N = 153) gerados por retrocruzamento, nenhum era portador do transgene (Nesperado = 85; Nobservado = 0; X2 = 348,185; p < 0,0001) É possível que o segmento genômico em que houve inserção do vetor lentiviral que carrega o transgene UBC-CreESR1 esteja ligado ao loco de Tsc1 no cromossomo 2 do camundongo, segregando juntos. O tratamento com 4-hidroxitamoxifeno de animais heterozigotos e portadores do transgene aumentou a quantidade de TSC1 no estriado (p < 0,05) e o cerebelo não apresentou alteração. É possível que mecanismos transcricionais ou traducionais, funcionais no estriado, tenham favorecido o aumento de TSC1 de forma dependente de 4-hidroxitamoxifenoTuberous sclerosis complex (TSC) is a genetic disorder that can affect any specific organs. In general, lesions are caused by biallelic inactivation of the tumor suppressor genes Tuberous Sclerosis Complex 1 (TSC1) or 2 (TSC2). On the other hand, in cortical and subcortical brain regions, lesions associated with neuronal migration and arborization failures can be explained by TSC1 or TSC2 haploinsufficiency. Brain cortical lesions commonly cause refractory epilepsy, which, in turn, may be associated with intellectual disabilities and behavioral disorders. These medical conditions may be present in TSC patients without detectable anatomic lesion on magnetic resonance images. TSC1 and TSC2 genes encode hamartin and tuberin, also known as TSC1 and TSC2, respectively. They act together in a cytosolic molecular complex that inactivates small GTPase Rheb, which is a mammalian target of rapamycin (mTOR) activator, regulating diverse cellular processes such as proliferation, differentiation, growth, migration and metabolism. With the hypothesis that the amount of TSC1 or TSC2 in the neuron can change its function depending on the metabolic state, the overall objective of this study was to characterize TSC1 and TSC2 expression patterns and activity in two mice models of induced neurodegeneration; and check whether TSC1 reduction changes dopaminergic neurons damage extent in a hemiparkinsonins model. For the first model, five brain structures from mice fed with high fat diet showed alterations in Tsc1 and/or Tsc2 mRNA, or oxidative stress signals. Reduction of Tsc1 and Tsc2 transcripts in the cerebral cortex was dependent on fasting performed immediately prior to euthanasiaThere was evidence of oxidative stress in the cingulate cortex. Increase in mRNA was observed in the hippocampus (Tsc1 and Tsc2) and striatum and hypothalamus (Tsc1), although independent of the fasting, suggesting that this effect is related to the high fat diet. In hemiparkinsonism model, adult mice subjected to intracerebral injection of 6-hydroxydopamine had decreased levels of S6 in the brain treated side compared to the contralateral segment (p = 0.004, r = 0.8795; Pearson test, CI: 95 %), without alterations in TSC1 nor TSC2. Using imunoperoxidase analysis, we described TSC1 expression in the striatum, entopeduncular and arcuate nuclei, and TSC2 in the thalamus and hypothalamus, independently from the 6-OHDA lesion. To obtain a mouse model without TSC1 postnatal expression in different brain regions, independently of the cell type, we performed crosses between transgenic mouse strain in which the Tsc1 gene contains lox sequences in introns 16 and 18 and strain with Tsc1 wild-type (WT) and the transgene for expression of Cre recombinase fused to the binding domain of the human estrogen receptor (ESR1) ligand, controlled by ubiquitin C (UBC) promoter expression. In F1, we obtained mice carrying the transgene UBC-CreESR1 and heterozygous for Tsc1 (Tsc1WT/flox). In F2, among animals homozygous Tsc1Flox/Flox (N=153) generated by backcrossing, none was carrying the transgene (Nexpected = 85; Nobserved = 0; X2= 348.185, p <0.0001) It is possible that the genomic segment containing the lentiviral vector insertion bearing UBC-CreESR1 transgene is linked to the TSC1 region on mouse chromosome 2, and they segregate together. Treatment with 4-hydroxytamoxifen in animals heterozygous and positive for the transgene showed increased TSC1 in the striatum (p <0.05), while there was no change in the cerebellum. It is possible that transcriptional or translational functional striatum mechanisms favored TSC1 increasing, in a 4-hydroxytamoxifen-dependent manner
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Silva, Crysthiane Saveriano Rubião. "Apoptose precoce, proliferação celular sincrônica tardia e perfil de expressão de proteínas ao complexo esclerose tuberosa e às doenças renais policísticas durante tubulogênese in vitro." Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/5/5160/tde-01082013-145925/.
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O complexo esclerose tuberosa (CET) e as doenças renais policísticas autossômica dominante (DRPAD) e autossômica recessiva (DRPAR) são doenças monogênicas associadas a cistogênese renal. Os produtos dos genes mutados nessas enfermidades, respectivamente tuberina e hamartina para CET, policistina-1 (PC1) e policistina-2 para DRPAD, e poliductina/fibrocistina para DRPAR, modulam proliferação, diferenciação, apoptose, crescimento e/ou migração celular. Neste estudo empregamos um sistema tridimensional de cultura de células IMCD para caracterizar os perfis de expressão dessas proteínas durante a tubulogênese. Usando uma matriz de colágeno tipo I/Matrigel e fator de crescimento de hepatócito (HGF), a formação de estruturas alongadas se iniciou dois dias após o plaqueamento in vitro (2 DIV), ao passo que o desenvolvimento de lúmen ocorreu entre 10-14 DIV. A marcação para caspase-3 ativa foi mais intensa nas fases iniciais da tubulogênese, enquanto a marcação para Ki-67 foi uniformemente pronunciada em estágios mais tardios. A tuberina e a hamartina apresentaram expressão citoplasmática e co-localização acentuada em 6 e 12 DIV. A PC1 apresentou maior expressão nas porções ramificadas dos túbulos que nas não ramificadas no 12 DIV, um padrão não verificado para a PC2. Estas proteínas exibiram expressão citoplasmática, assim como expressão ocasional e pontual na membrana plasmática. PD1 também apresentou expressão citoplasmática. Nossos dados sugerem que a apoptose e a ciclagem celular sincrônica durante a tubulogênese in vitro são mais acentuadas, respectivamente, em fases mais precoces e mais tardias da formação tubular. Nossos achados demonstram, além disso, que as proteínas relacionadas ao CET e às DRPs são expressas in vitro durante a tubulogênese, apoiando um papel importante para a interação tuberina-hamartina na formação tubular, e são consistentes com o padrão de expressão diferencial da PC1 observado durante a nefrogêneseTuberous sclerosis complex (TSC) and autosomal dominant and recessive polycystic kidney diseases (ADPKD and ARPKD) are monogenic diseases associated with renal cystogenesis. The products of the genes mutated in these disorders, respectively tuberin and hamartin for TSC, and polycystin-1 (PC1), polycystin-2 (PC2) and polyductin/fibrocystin (PD1) for PKD, modulate cell proliferation, differentiation, apoptosis, growth and/or migration. We have employed an IMCD tridimensional cell culture system to characterize their expression profiles along tubulogenesis. Using a type I collagen/Matrigel matrix and hepatocyte growth factor (HGF), the formation of elongated structures initiated 2 days after in vitro plating (2 DIV) while lumen developed between 10-14 DIV. Active caspase-3 labeling was more intense in initial phases of tubulogenesis while Ki-67 staining was uniformly pronounced in later stages. Tuberin and hamartin showed cytoplasmic expression and marked co- localization at 6 and 12 DIV. PC1 displayed higher expression in branching than non- branching portions of the tubules at 12 DIV, a pattern not verified for PC2. These proteins presented cytoplasmic and occasional, punctate membrane expression. PD1 also showed cytoplasmic expression. Our data suggest that apoptosis and synchronous cell cycling during in vitro tubulogenesis are more remarkable, respectively, in early and later steps of tubule formation. In addition, our findings demonstrate that the TSC and PKD proteins are expressed in vitro during tubulogenesis, supporting an important role for tuberin-hamartin interaction in tubular formation, and are consistent with the differential PC1 expression pattern observed during nephrogenesis
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Pons, Bennaceur Alexandre. "Les mécanismes antiépileptiques de l’AppCH2ppA dans la sclérose tubéreuse de Bourneville." Thesis, Aix-Marseille, 2018. http://www.theses.fr/2018AIXM0303.
Full textAbstract:
La Sclérose Tubéreuse de Bourneville est une pathologie génétique rare qui se caractérise par la survenue de crises épileptiques précoces à l’origine du développement de nombreux troubles neurologiques tels que des symptômes autistiques ou des retards mentaux. Les épilepsies retrouvées dans la Sclérose Tubéreuse de Bourneville sont souvent résistantes aux traitements pharmacologiques disponibles soulevant la nécessité de trouver de nouvelles approches médicamenteuses plus efficaces pour traiter les patients. Dans cette étude nous avons mis en évidence que l’AppCH2ppA est une molécule efficace pour bloquer la survenue des crises épileptiques dans un modèle de souris pour la Sclérose Tubéreuse de Bourneville ainsi que sur des résections chirurgicales de tissu provenant de patients humains atteints par la Sclérose Tubéreuse de Bourneville. Nous avons montré que les propriétés antiépileptiques de l’AppCH2ppA s’appuient sur une libération autocrine d’adénosine par les neurones de la couche IV du cortex somatosensoriel et d’une activation consécutive des récepteurs à l’adénosine de type A1. Cette activation a lieu spécifiquement au niveau du compartiment postsynaptique et est responsable d’une activation de conductances potassiques et d’une diminution de l’excitabilité des neurones. L’administration d’AppCH2ppA n’est associé à aucun effet secondaire notables sur la santé des souris. Ainsi l’AppCH2ppA semble être un outil thérapeutique prometteur et peu risqué qui stimule des mécanismes antiépileptiques endogènes naturellement sollicités par le cerveau et efficaces pour stopper et limiter la survenue des crises épileptiquesTuberous Sclerosis Complex (TSC) is a rare genetic disease characterized by the presence of epilepsies that appear early and in the life of patients and are responsible for the development of several neurological disorders such as autistic symptoms or mental retardations.In TSC, epileptic seizures often resist to pharmacological approaches raising the importance to find new molecules to treat more efficiently the patients.In this study we showed that AppCH2ppA is an effective molecule to block the onset of epileptic seizures in a mouse model for Tuberous Sclerosis as well as on human patients tissues.We have shown that AppCH2ppA nduce an autocrine release of adenosine by the spiny stellate cells present in the layer IV of the somatosensory cortex. This release is responsible for a subsequent activation of adenosine A1 receptors that occur specifically in the postsynaptic compartment of neurons and is responsible for an activation of potassium channels and a decrease of the excitability of neurons. The administration of AppCH2ppA is not associated with any significant side effects on mouse health. Thus, AppCH2ppA appears to be a promising and low-risk therapeutic tool that stimulates an endogenous antiepileptic pathway that is naturally used in the brain and that is efficient to stop and limit the appearance of epileptic seizures
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SAVVIDOU, SOTIRA. "Les manifestations oculaires de la sclerose tubereuse de bourneville." Lille 2, 1988. http://www.theses.fr/1988LIL2M127.
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SAURAT, NATHALIE. "Syndrome epileptique dans la sclerose tubereuse de bourneville : a propos d'un cas particulier, interet d'une prise en charge precoce sur le plan diagnostique et therapeutique." Toulouse 3, 1988. http://www.theses.fr/1988TOU31052.
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ENRICO, MARIE-FRANCE. "Epilepsie et sclerose tubereuse de bourneville : a propos de 55 cas." Lyon 1, 1994. http://www.theses.fr/1994LYO1M008.
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MAHE, JEAN-FRANCOIS. "Les formes pulmonaires de la sclerose tubereuse de bourneville : a propos d'un cas masculin ; revue de la litterature." Lyon 1, 1989. http://www.theses.fr/1989LYO1M366.
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SICSIC, ALAIN. "Les atteintes renales de la sclerose tubereuse de bourneville : a propos d'une observation." Nice, 1993. http://www.theses.fr/1993NICE6544.
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MEDIONI, DAN. "Contribution a l'etude de l'histoire naturelle du rhabdomyome cardiaque : a propos de deux observations." Montpellier 1, 1993. http://www.theses.fr/1993MON11105.
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