Grant: Project Grant

Tuberous Sclerosis Complex (TSC) is a genetic disease that affects more than two million people. TSC patients develop abnormal growths or "lesions" in many organs. About 80% of TSC patients have kidney disease, which includes cysts and a lesion known as renal angiomyolipoma (R-AML), a leading cause of chronic kidney disease and death due to TSC. Only one drug (rapamycin) slows TSC progression, but it does not kill the cells that make the lesions, and many patients fail to respond to rapamycin. Patients with TSC need new therapies that will eradicate their lesions. Yet, a major bottleneck for the therapy development has been a lack of effective cell and animal models of TSC. Recently, our lab made human TSC stem cell models and used them to make mini-kidneys that develop cysts and display many characteristics of R-AML in a culture dish and all the characteristics of R-AML when transplanted into mouse kidneys. Using these mini-TSC kidneys, we identified cells from the nervous system that contribute to TSC renal disease and R-AML formation and confirmed this finding using human TSC surgical specimens. We developed the first genetic mouse model that captures aspects of R-AML. We also used our TSC stem cell models to discover new drugs that kill TSC cells grown in culture dishes and grown in a TSC mouse model. Now, we propose to perform three studies in parallel. In the first study, we will assess the different cell types that contribute to TSC kidney disease using our mini-kidney model and patient cells transplanted into mouse kidneys. This transplantation model will also be used for drug testing. In studies 2 and 3, we will use complementary mouse models of TSC that we developed to map the developmental origin of TSC kidney disease, learn about lesion growth and whether the lesions will migrate to other organs. This project will reveal the cells and molecules that drive TSC kidney disease; knowledge that is critical for the development of new therapies.