Project Summary This proposal is a five-year career development plan that will support my transition to an independent career as a neuroscientist and neuro-ophthalmologist focused on understanding the mechanisms of neurodegeneration in the visual system and developing therapies for vision restoration. I am currently an Instructor in the Department of Neurology. Under the mentorship of Dr. David Gutmann, MD, PhD, and with the guidance of my scientific advisory committee, I will receive didactic and practical training to expand my scientific and clinical expertise, as well as improve my skills in collaboration, communication, lab management, grantsmanship, and leadership needed for an independent scientific career. In addition, I will build upon my preliminary experiments to delineate the mechanisms underlying estrogen-mediated (extrinsic) and cyclic-AMP (cAMP)-mediated (intrinsic) vulnerability of retinal ganglion cells (RGCs) that collectively culminate in RGC death and vision loss in an authenticated mouse model of optic pathway glioma (OPG). Neurofibromatosis type 1 (NF1) is a cancer predisposition syndrome in which 15-20% of children develop an OPG, a low-grade astrocytoma of the visual pathway. Of these affected children, 30-50% will experience vision loss due to RGC death. Moreover, girls with NF1-OPG are 3-5 times more likely to require treatment due to vision loss than boys, despite a relatively equal incidence of OPGs in both sexes. These findings suggest that vision loss from NF1-OPG is controlled by mechanisms that are sexually dimorphic. Leveraging authenticated mouse models of Nf1-OPG developed by the Gutmann laboratory, I identified estrogen-activated glial production of interleukin 1β (IL-1β) as a possible extrinsic mechanism for RGC death due to Nf1-OPG. Building upon previous findings demonstrating that defective cAMP production predisposes Nf1-mutant RGCs to injury, I also identified cAMP-dependent protein kinase inhibitor α (PKIα) as a potential mediator of the intrinsic RGC vulnerability in the setting of Nf1-OPG. Based on these exciting preliminary results, I hypothesize that estrogen- mediated glial expression of IL-1β is neurotoxic to Nf1-mutant RGCs with a pre-existing vulnerability to death conferred by reduced cAMP-dependent survival signaling. In this proposal, I have designed experiments to (1) define the necessity of estrogen-induced IL-1β in Nf1-OPG-mediated RGC death, (2) determine whether PKA inhibition heightens RGC vulnerability in the setting of Nf1-OPG, and (3) execute preclinical studies to evaluate estrogen suppression and cAMP restoration as potential neuroprotective strategies. The goals of the proposed experiments aim to (1) expand our understanding of molecular mechanisms underlying RGC death and vision loss in Nf1-OPG, (2) identify targets for the development of vision restorative therapies for children with vision loss due to NF1-OPG, and (3) lay the groundwork for my future studies and career developmen...