Tuberous sclerosis (TS) is an autosomal dominant disease that causes widespread benign tumors in many tissues including the brain, lung, kidney, skin, eyes, and teeth. Although TS is rarely fatal it causes debilitating complications such as seizures, mental retardation, and heart obstruction. Tumors can arise throughout life, and in severe cases cause kidney or heart failure in adults. The disease is highly prevalent, affecting ~1/6000 individuals, or about 50,000 in the US population. There is no cure. Most cases of TS are caused by loss of function in one of two genes, TSC1 orTSC2, which encode a protein complex. The TSC1/2 complex mediates many of its effects by inhibiting the activity of Rheb, an essential activator of the Target-Of-Rapamycin (TOR) kinase, which is a central regulator of cell growth. TOR controls diverse metabolic processes required for cell growth including protein synthesis, nutrient import, autophagy, and transcription. It has two well-characterized targets in humans, S6K and 4EBP, but genetic analysis in Drosophila and mice indicate that these targets cannot account for the striking overgrowth phenotypes that occur in tuberous sclerosis. Moreover, it is has not been demonstrated that all of the downstream effects of TSC mutation are mediated via Rheb and/or TOR. Hence the identification and characterization of additional effectors of TSC1/2 complex is required to advance our understanding of the molecular and cellular basis of this disease. This project will use genetic and proteomic approaches in Drosophila and human cells to: 1) Evaluate the hypothesis that the TSC1/2 complex mediates all of its effects via Rheb and TOR, and;2) Identify and characterize new gene products required for TSC1/2 and Rheb function. Such genes are expected to be effectors of deregulated cell growth in tuberous sclerosis, and as such constitute potential targets for diagnosis and treatment of the disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS058230-05
Application #
7848110
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Morris, Jill A
Project Start
2006-09-10
Project End
2011-09-30
Budget Start
2010-06-01
Budget End
2011-09-30
Support Year
5
Fiscal Year
2010
Total Cost
$374,182
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
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