This K01 proposal describes a five-year research and training plan that will facilitate the transition of Dr. Hilaire Lam to an independent academic investigator in the field of mitochondrial dynamics in kidney disease. Dr. Lam has a strong background in molecular biology and pathological processes. As a postdoctoral fellow she investigated the molecular mechanisms and aberrant metabolism supporting kidney cystogenesis in tuberous sclerosis complex (TSC). While mTORC1 inhibitors slow TSC disease progression, disease activity resumes soon after treatment cessation, necessitating life long treatment. Therefore, Dr. Lam seeks to identify more durable therapeutic responses through a better understanding of mitochondrial dynamics in TSC. The candidate has confirmed that TSC-deficient cells are characterized by increased mitochondrial content, and discovered that Tsc2-deficient cells depend on the upregulation of certain adaptive molecules (p62/SQSTM1 and miR-21) to maintain mitochondrial integrity. The role of mitochondrial dynamics, particularly fission, a process directly regulated by mTORC1 in the development and progression of mTORC1-driven kidney cystogenesis represents a key knowledge gap. Dr. Lam will address the central hypothesis that mTORC1-hyperactivated cells depend on STAT3 to regulate mitochondrial function and fission to support metabolic reprogramming and cyst formation. This hypothesis will be addressed in the following Specific Aims: 1. To determine the effects of Stat3 signaling on mitochondrial dynamics and metabolic reprogramming in Tsc2-deficient cells.
Aim 2 : To determine the dependence of cyst formation and progression on mitochondrial fission. The significance and innovation of this project is to identify mitochondrial targets to increase the durability of therapy of the renal manifestations of TSC. The contribution of mitochondrial fission to cellular metabolism may have translational relevance to other cystic renal diseases. Dr. Lam will receive mentorship from her outstanding scientific advisory committee composed of distinguished scientists with expertise related to key areas of this proposal including mitochondria (Finkel), metabolism (Asara), signaling (Manning) and kidney redox homeostasis (Pal) and polycystic kidney disease (Zhou). The Department of Medicine is committed to Dr. Lam's success and will continue to provide resources for her as a member of the faculty. The candidate's mentor, Dr. Elizabeth Henske, is a NIH funded researcher in the field of TSC/LAM and metabolism with experience training and transitioning mentees to independence. A detailed career development and training plan is presented that includes research, coursework, readings, seminars and presentations at scientific meetings. The candidate details a timeline for completion of research aims, preparation of manuscripts and R01 application. The expertise and skills gained from this K01 will prepare Dr. Lam to obtain the R01 funding necessary to launch her career focused on mitochondrial dynamics in disease.
Patients with tuberous sclerosis complex (TSC) develop renal disease including cystic kidneys, as a result of TSC1 or TSC2 loss and subsequent aberrant mTORC1 activation in the renal epithelium. My central hypothesis is that mTORC1-hyperactivated cells depend on Stat3 to regulate mitochondrial function and fission to support metabolic reprogramming and cyst formation. A key translational corollary of this hypothesis is that targeting these critical mitochondrial alterations will prevent cyst formation and progression with direct translational relevance to other cystic kidney diseases associated with hyperactive mTORC1, including autosomal dominant polycystic kidney disease ADPKD.
