Project Summary The degeneration of retinal ganglion cells (RGCs) causes irreversible blindness in millions of people worldwide. Efforts to develop treatment which target RGCs and prevent their degeneration have been hampered by an incomplete understanding of this process. A recent screen of ~1000 kinases and phosphatases in our lab has identified several novel contributors to RGC death after optic nerve injury. A group of these proteins are related to cellular metabolism, a known contributor to RGC death. This project will explore how these proteins contribute to metabolic dysfunction within injured RGCs. The most exciting kinase identified by our screen is Liver Kinase B1 (LKB1). LKB1 is a master kinase that activates various downstream pathways in other cell types but its function in RGCs is uncharacterized. A very promising possibility is that LKB1 may be one of the principal modulators of RGC metabolism under stress. However, as a result of its promiscuous activity, this proposal is necessary to decipher the exact mechanism of LKB1 signaling in RGCs. Through use of a flexible, viral mediated knockout strategy devised by our lab, we will determine the mechanism of LKB1 pathway mediated degeneration and its relevance in glaucoma. By pairing targeted assays with single cell RNA sequencing and metabolomic approaches, we will reveal the causative metabolic changes that cause RGC death and hope to translate these findings into actionable clinical therapeutics. Under the tutelage of Dr. Zhigang He, the experiments proposed here will grow my technical abilities and my scientific thinking, paving the way for me to become an independent investigator.

Project Narrative Following optic nerve injury, a complex set of responses in RGCs and other cell types in the retina determine RGC fate. Modulation of RGC-intrinsic processes is a promising therapeutic strategy that has not been realized because of an incomplete understanding of how these processes cause RGC degeneration. In this proposal, the contributors to metabolic dysfunction will be studied in detail to determine how they function and how to prevent metabolic related RGC death.