Evaluating Mitochondrial Quality Control in the Outflow Facility

PROJECT SUMMARY This is a K08 Mentored Clinician Scientist Development Award application for Anh Pham, MD, PhD, who is an Assistant Professor of Ophthalmology at the Bascom Palmer Eye Institute (BPEI) with a career goal of becoming an independent clinician-scientist in the field of glaucoma. Her research focus examines the metrics of mitochondrial health, including morphology, biogenesis, selective removal, and genomic stability, in the outflow facility between healthy and glaucoma patients. The research proposal seeks to identify mitochondrial dysfunction as an important mechanism for the development of ocular hypertension. The long-term goal of this project is to acquire the scientific skills needed to enhance our understanding of the regulatory mechanisms controlling mitochondrial health in the outflow facility and to develop mitochondria targeted therapies to improve intraocular pressure homeostasis. The scientific objective is to test the hypothesis that impaired mitophagy, the selective clearance of damaged mitochondria, contributes to the accumulation of mitochondrial dysfunction in glaucoma outflow facility. The project will utilize in vitro, ex vivo, and in vivo models of the outflow facility to examine the intrinsic relationship between mitochondrial health and TM physiology. There are three focused aims to test this hypothesis: 1) Compare mitochondrial function between healthy and glaucoma TM in cell culture; 2) Simulate ocular hypertension in an ex vivo model to develop a tissue platform for examining the protective effects of mitophagy induction in TM physiology; 3) Develop a mouse model with mitochondrial dysfunction in the outflow facility as a potential model for aging in the eye and ocular hypertension. Results of the proposed research will establish the foundation for an R01 application on mitochondrial quality control in the anterior segment. The career development objective is to develop the mentorship and expertise to become a productive and independent clinician-scientist. Dr. Pham has assembled a mentorship team consisting of Dr. Sanjoy K. Bhattacharya, an expert in TM biology and Dr. Carlos Moraes, an expert in in vivo models of mitochondrial dysfunction. Additionally, she has identified key collaborators and consultants including Drs. Felipe Medeiros, Richard K. Lee, Padmanabhan Pattabiraman, and Weiming Mao. She will meet regularly with her mentors and advisors to discuss career development, attend pertinent university seminars and workshops, present research annually at national conferences, consistently submit work for publication, and apply for extramural funding. The extensive clinical and scientific resources at BPEI, the world-class faculty on the mentorship and advisory committee, and the dedicated institutional commitment will provide Dr. Pham with the support needed to promote scientific independence in the study of mitochondrial health in the anterior segment.