Background: Tuberous Sclerosis (TSC) is caused by mutation in either TSC1 or TSC2 gene and is characterized by the formation of hamartomas in a variety of organs. Common clinical symptoms in TSC patients include seizures, mental retardation, autism, and renal complications, among which renal complications are the most frequent cause of tuberous sclerosis-related death characterized by the development of a variety of renal tumors. Spontaneous bleeding is the most common complication in patients with renal tumors and results in significant morbidity and mortality, and currently there is no effective cure for this. Despite the tremendous progress in the TSC field in the last decade, very little is known about the role of TSC in the pathogenesis of renal cancer development, and the cooperative oncogenic events in TSC-mediated renal tumorigenesis.

Research Project: This proposal aims to elucidate the molecular pathogenesis of TSC-related renal tumorigenesis and to provide novel insights of targeted therapies against renal complications in TSC patients. An integrative cancer biological approach will be pursued to study the exact role of FoxO transcriptional factors, a key surrogate of the PI3K cancer signaling pathway in TSC-related renal tumorigenesis and to identify FoxO targets mediating the biological functions of TSC-related renal tumorigenesis. Because renal tumors affect most TSC patients and renal complication represents the most frequent cause of tuberous sclerosis-related death, this proposal will significantly advance our understanding of the molecular pathogenesis of TSC-related renal tumorigenesis and help expand the development of novel drugs or serve biomarkers against renal complications in TSC patients.

Training Program: My desire to conquer TSC disease has been a long-standing personal mission that was ignited by the loss of my grandfather to TSC when I started my graduate career. Since then I have been dedicated to TSC research in both my graduate and postdoctoral careers, with the goal of applying such understanding of fundamental molecular processes to the development of effective and novel drugs for the treatment of TSC patients. Fortunately, with the outstanding mentorship and scholarship support I received throughout my career, my TSC research has been highly productive and resulted in a dozen or so publications in top journals. I firmly believe the TSCRP Career Transition Award will be critical in facilitating my further career development toward becoming an independent TSC researcher. Regarding my training program, in the first 2-year mentored phase of this grant, I wish to remain in this highly interactive and scientifically rigorous mentored environment in Dr. DePinho's lab at the Dana-Farber Cancer Institute, where I have access to resources that are necessary for the full realization of my program, which will form the basis of my independent career. My mentor, Dr. DePinho, will continue to provide guidance for improving my skills in executing increased project management responsibilities and grant writing. The Harvard community offers extensive relevant expertise and collaborative opportunities. I plan to transition toward an independent faculty position within 2 years following the initiation of this grant. I will seek a research environment with a strong basic science focus in the fields of cancer biology, cancer signaling, and stem cell biology complemented by close collaboration with physician-scientists in order to translate discoveries into relevant advances for treating TSC disease. An important component of my program will be my continued participation in a multidisciplinary consortium of PI3K/TSC/mTOR researchers currently in the process of addressing a series of programmatic initiatives.