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Principal Investigator: Elizabeth P Henske
Organization: BRIGHAM AND WOMEN'S HOSPITAL
Fiscal Year: 2024
Award: $368,893
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Abstract
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by germline loss-of-function
mutations in TSC1 or TSC2. Renal disease, which includes cysts, angiomyolipomas, and renal cell carcinoma,
is a major source of morbidity and mortality for both children and adults with TSC. mTORC1 inhibitors have
partial, cytostatic effects on TSC-associated tumors, so continuous and potentially lifelong therapy is required,
often beginning in early childhood. The death of two children from serious infection in a recent trial of mTORC1
inhibition for TSC highlights the unmet need for novel therapies that eliminate TSC-associated tumor cells.
The TSC1/TSC2 protein complex inhibits mTORC1. Multiple components of the TSC signaling network can
localize to the lysosomal membrane, including mTOR, Rheb, TSC1, and TSC2. Lysosomes are highly dynamic
organelles with both degradative and signaling functions. We have found that nuclear levels of the transcription
factor TFEB, a master regulator of lysosomal biogenesis, are elevated in TSC1-deficient and TSC2-deficient
cells, in a mouse model of TSC renal disease, and in human TSC tumors. This is unexpected, because mTORC1
phosphorylates TFEB and TFE3, leading to their cytoplasmic sequestration. We have also found that TFEB is
required for the proliferation of TSC2-deficient cells, in vitro and in vivo. These and other preliminary data lead
to our central hypothesis that hyperactivation of TFEB and TFE3 leads to a lysosome-dependent increase in cell
proliferation in TSC. This hypothesis will be tested in three Aims:
Aim 1. To identify the mechanisms of nuclear localization of TFEB and TFE3 in TSC2-deficient cells.
Aim 2. To identify compounds that induce TFEB and TFE3 to move to the cytoplasm in TSC2-deficient cells.
Aim 3. To determine the in vivo impact of TFEB and TFE3 on cell proliferation and renal cystogenesis in TSC.
We expect this project to have scientific and preclinical impact by elucidating the roles of TFEB and lysosomal
biogenesis in TSC-associated renal disease, with the potential for clinical translation to prevent and/or eliminate
TSC-associated renal tumors.
Terms: <0-11 years old><21+ years old><AQP-CD><AQP2 protein><Adult><Adult Human><Affect><Age><Angiomyolipoma><Angiomyolipoma of the Kidney><Basal Transcription Factor><Basal transcription factor genes><Biogenesis><Bourneville Disease><Bourneville Phakomatosis><Bourneville syndrome><Bourneville-Brissaud disease><Bourneville-Pringle syndrome><Cadherins><Cancer Genes><Cancer-Promoting Gene><Carcinoma Cell><Cell Body><Cell Communication and Signaling><Cell Growth in Number><Cell Multiplication><Cell Nucleus><Cell Proliferation><Cell Signaling><Cells><Cellular Proliferation><Cessation of life><Child><Child Youth><Children (0-21)><Clinical><Collecting Cell><Complex><Cyst><Cystic kidney><Cytoplasm><Cytostatic Agents><Cytostatic Drugs><Cytostatics><Data><Death><Disease><Disorder><Distal><Drug Screening><Duct><Duct (organ) structure><Ductal Cell><Ductal Epithelial Cell><Enzyme Gene><Enzymes><Epiloia><Event><Exocytosis><Extracellular Space><FDA approved><FK506 Binding Protein 12-Rapamycin Associated Protein 1><FKBP12 Rapamycin Complex Associated Protein 1><FRAP1><FRAP1 gene><FRAP2><Family><GTP Phosphohydrolases><GTPases><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genetic><Genetic Transcription><Germ Lines><Goals><Grawitz Tumor><Guanosine Triphosphate Phosphohydrolases><Guanosinetriphosphatases><Hamartin><High Throughput Assay><Histologic><Histologically><Human><Hyperactivity><Hypernephroid Carcinoma><Hypernephroma><In Vitro><In vivo analysis><Infection><Intercellular Space><Intracellular Communication and Signaling><Kidney><Kidney Cyst><Kidney Diseases><Kidney Failure><Kidney Insufficiency><Kidney Neoplasms><Kidney Tumor><Kidney Urinary System><Lead><Lysosomes><Malignant Epithelial Cell><Measurement><Mechanistic Target of Rapamycin><Membrane><Modern Man><Morbidity><Morbidity - disease rate><Nephroid Carcinoma><Nephropathy><Nuclear><Nucleus><Oncogenes><Organelles><Origin of Life><Pathogenesis><Patients><Pb element><Phosphorylation><Pre-Clinical Model><Preclinical Models><Pringle disease><Process><Proliferating><Protein Phosphorylation><RAFT1><RNA Expression><Renal Adenocarcinoma><Renal Angiomyolipoma><Renal Cell Adenocarcinoma><Renal Cell Cancer><Renal Cell Carcinoma><Renal Cyst><Renal Disease><Renal Failure><Renal Insufficiency><Renal Neoplasms><Renal Tumor><Role><Seizures><Signal Transduction><Signal Transduction Systems><Signaling><Site><Solid><Source><Subependymal Giant Cell Astrocytic Neoplasm><Subependymal Giant Cell Astrocytic Tumor><Subependymal Giant Cell Astrocytoma><TSC1><TSC1 gene><TSC1/2><TSC1/2 gene><TSC1/TSC2><TSC2><TSC2 gene><TSC2/TSC1><TSC4><TSC4 Gene><Testing><Therapeutic><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><Transforming Genes><Tuberin><Tuberous Sclerosis><Tumor Cell><WCH-CD><adenoma sebaceum><adult youth><adulthood><ages><aquaporin-2><aquaporin-CD><autosome><biological signal transduction><cerebral sclerosis><clinical translation><clinically translatable><collecting duct water channel><constitutive expression><constitutive gene expression><early childhood><epiploia><gene testing><gene-based testing><genetic testing><guanosinetriphosphatase><heavy metal Pb><heavy metal lead><hereditary multiple system hamartomatosis><high throughput screening><improved><in vivo><in vivo evaluation><in vivo testing><inhibitor><insight><kidney adenocarcinoma><kidney disorder><kids><loss of function mutation><mTOR><mammalian target of rapamycin><member><membrane structure><mortality><mouse model><murine model><neoplastic cell><neurinomatosis centralis><neuromatosis universalis><neurospongioblastosis diffusa><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><phacomatosis><pharmacologic><pre-clinical><preclinical><prevent><preventing><protein complex><renal><renal disorder><sclerosis tuberosa><small molecule><social role><spongioblastosis circumscripta><transcription factor><tuberose sclerosis><tuberous sclerosis 1><tuberous sclerosis complex><tumor><young adult><young adulthood><youngster>