Elizabeth Henske, MD
Professor, Department of Medicine, Harvard Medical School
DF/HCC Program AffiliationKidney Cancer
Research AbstractThe primary focus of my laboratory is the pathogenesis of tuberous sclerosis complex (TSC) and the related disorder, lymphangioleiomyomatosis (LAM). TSC is a multisystem disorder in which the manifestations can include tumors in the brain, heart, kidney, and skin, as well as mental retardation and autism. My laboratory has a particular interest in the renal manifestations of TSC (cysts, angiomyolipomas, and carcinomas) and in the pulmonary manifestation, LAM. About 30% of women with TSC develop LAM, which is an unusual lung disease in which benign-appearing smooth muscle cells proliferate extensively in the lungs, leading to cystic, emphysema-like lung destruction and lung failure. LAM pathogenesis appears to involve one of the most unusual pathogenic mechanisms in human disease: the metastasis of histologically benign cells.
The protein products of the TSC1 and TSC2 genes (hamartin and tuberin, respectively) physically interact to inhibit the activity of the kinase, TORC1. This mTOR inhibition is achieved the small GTPase Rheb which is regulated by the GAP (GTPase activating protein) region of TSC2. A great deal of attention has been focused on the role of TORC1, which is inhibited by Rapamycin, in the pathogenesis of TSC and LAM. A key area of uncertainty is whether Rheb has TORC1-independent targets that are disease-relevant.
Currently the laboratory is examining 1) the mechanisms through which estrogen may promote the metastasis of TSC2-null cells, thereby promoting LAM pathogenesis, 2) the role of the TSC pathway in neural development, using a Drosophila model, and 3) the connections between the TSC proteins and the Birt-Hogg-Dube (BHD) protein. BHD (like TSC) is associated with renal cell carcinoma and cystic lung disease. In S. Pombe we have found that the BHD homolog functions in the TOR signaling pathway, but in opposition to the TSC proteins.