The Role of Mechanosensitive Ion Channels in Glaucoma

This proposal describes a 5-year training program to develop an academic career focused on investigating the role of mechanosensitive ion channels in glaucoma. My long-term goal is to discover new strategies for treating glaucoma by understanding the mechanisms of mechanosensation in the eye. Although intraocular pressure (IOP) is the most significant risk factor for glaucoma, the identify and function of mechanosensitive proteins in the eye remain largely unknown. I will use human genetic analyses, in vitro molecular and electrophysiological approaches, and in vivo mouse models of glaucoma to study the role of mechanosensitive ion channels in mediating retinal ganglion cell (RGC) death in glaucoma. Preliminary results have identified human variants in mechanosensitive ion channel genes associated with glaucoma risk. I hypothesize that mechanosensitive ion channels in retinal cells sense IOP and mediate RGC death in glaucoma, and that human variants confer differential risk in these functions. Aim 1 determines the contribution of mechanosensitive ion channels to pressure-activated currents in retinal cells in vitro upon mechanical stimulation. Aim 2 investigates how human variants of mechanosensitive ion channel genes alter channel function in a heterologous system. Aim 3 tests the role of mechanosensitive channels in a mouse model of glaucoma. The proposed studies have the potential to provide insight into how IOP leads to RGC death and identify novel therapeutic targets for glaucoma. With my graduate training in sensory neuroscience and electrophysiology, I am well equipped to conduct this research. My career development plan will allow me to 1) learn retinal physiology, 2) develop knowledge and technical expertise in the field of mechanosensation, 3) acquire experience with mouse models of glaucoma and 4) develop grantsmanship, leadership and managerial skills to lead an independent research team. I am supported by a committed team of mentors who are dedicated to advancing my career as an independent clinician scientist. I will work with retinal physiology expert Dr. Stephen Baccus, leaders in translational glaucoma research Dr. Jeffrey Goldberg, Dr. Yang Hu and Dr. Yang Sun, mechanosensation and ion channel experts Dr. Ardem Patapoutian, Dr. Miriam Goodman and Dr. Merritt Maduke, and human glaucoma genetics expert Dr. Janey Wiggs. This training will take place within the collaborative vision and neuroscience community at Stanford, with access to its extensive resources for research and career development. This research addresses a critical need to understand the mechanisms of mechanosensation in glaucoma and prepares me for a career as an independent NIH-funded investigator, with the ultimate goal of advancing these discoveries to the bedside to develop better treatments for this common blinding disease.