The role of impaired mitophagy and mitochondrial dysfunction in glaucomatous neurodegeneration

项目总结/文摘:

PROJECT SUMMARY/ABSTRACT: Primary open angle glaucoma (POAG), the most common form of glaucoma, is characterized by progressive loss of retinal ganglion cells (RGCs) and their axons, leading to irreversible vision loss. Elevated intraocular pressure (IOP) is the major risk factor for POAG. Unfortunately, the underlying pathological mechanisms responsible for IOP-induced glaucomatous neurodegeneration still remain unclear. The long-term goal of this proposal is to delineate the molecular pathways governing IOP-induced glaucomatous neurodegeneration and to develop an effective glaucoma treatment strategy. To this end, we have developed a novel glucocorticoid (GC)-induced and myocilin-associated mouse models of POAG, replicating human POAG phenotypes. Importantly, we have identified impaired mitophagy, accumulation of damaged mitochondria and inflammatory immune cells in the optic nerve of both human and mouse glaucoma. Based upon our preliminary data, we propose to: 1) examine the effect of IOP on mitophagy impairment and accumulation of damaged mitochondria using mouse and human POAG, 2) examine the role of impaired mitophagy on glaucomatous neurodegeneration and, 3) further identify whether enhancing mitophagy alleviates neurodegeneration and prevent RGC loss in mouse models of POAG. In the mentored phase, I will establish mouse models to study mitophagy in POAG including mitophagy reporter transgenic Mt-Keima mice, RGC-specific Parkin and ATG5 conditional knockout mice under the guidance of Dr. Gulab Zode (an expert in chronic ER stress and autophagy in trabecular meshwork). In collaboration with Dr. Denise Inman (an expert in the field of mitochondrial metabolism), I will enhance my understanding of mitochondrial dysfunction in mouse models of POAG. The mentored phase will also be supplemented by training with Dr. Abbot Clark (well-known leading glaucoma expert), who will provide assistance with human tissues as well as an additional training for my independent career. Furthermore, regular meetings with Dr. Paula Gregory who has tremendous experience in assisting young investigators will help me to develop independent career. During the independent phase, we will examine role of mitophagy on inflammatory neurodegeneration and determine whether inducing mitophagy (Urolithin A/Actinonin/Metformin/ Parkin overexpression) rescues GC or myocilin-associated POAG. Additionally, during the mentored phase, I will be having regular meetings with my advisory committee, attend scientific conferences, and continue my career development. I am in the ideal environment for the proposed research and for my career development as Dr. Zode has an established state-of-the-art facilities at the North Texas Eye Research Institute, and collaborations with renowned scientists, Dr. Val Sheffield, Dr. John Hulleman and Dr. Kevin Park. This will help me to set-up good collaborations, learn new techniques, and build an independent research laboratory at a well- established academic institution.