Identifying Novel Drug Targets for the Treatment of Tuberous Sclerosis Complex Using High Throughput Technologies
Final rept. 8 Dec 2004-7 Dec 2005
WHITEHEAD INST FOR BIOMEDICAL RESEARCH CAMBRIDGE MA
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In a patient with Tuberous Sclerosis Complex TSC, the problematic cells that initiate and constitute tumors have lost TSC1 or TSC2 function. A promising approach for treatment would be to target members of the pathway with which TSC12 proteins interact. In cultured drosophila cells, we proposed to rapidly identify genes whose RNAi-mediated reduction in expression 1 Prevents growthproliferation of TSC1 or TSC2-deficient cells without affecting normal cells. 2 Induces apoptosiscell death in TSC1 or TSC2-deficient cells without killing normal cells. 3 Reverts TSC1 or TSC2-deficient cells to a normal phenotype, as determined by measuring a reporter of cell growth pathway activation and cell morphology. We have 1 advanced genome-wide RNA interference living cell microarrays from proof-of-principle to a robust technology. 2 developed software to analyze these screens, a previously formidable challenge, and 3 completed genome-wide experiments on the scale required to complete the goals of this proposal. We will repeat these experiments under several experimental conditions in order to identify genes involved in the TSC pathway.
- Medicine and Medical Research