Mechanisms of Neuroregulation of Corneal Angiogenesis

摘要（来自原始申请）

ABSTRACT (From Original Application) This proposal describes a 3-year training program for the development of an academic career focused on understanding the mechanisms of neuroregulation of corneal angiogenesis. The candidate Jia Yin, M.D., Ph.D. is an Assistant Professor of Ophthalmology at Massachusetts Eye and Ear Infirmary, Harvard Medical School. She has scientific training in the field of corneal wound healing, angiogenesis, and immunology, and clinical training in corneal diseases. Dr. Yin’s long-term goal is to advance the scientific understanding and clinical treatment of blinding corneal diseases. In this 3-year career development plan, she proposes to1) enhance scientific knowledge and techniques in neuroscience, angiogenesis and immunology, 2) hone grantsmanship, and 3) develop leadership and managerial skills, through coursework, seminars, and meetings with clearly defined milestones. The advisory committee includes mentor Dr. Reza Dana, renowned clinician scientist in corneal diseases and ocular immunology, and co-mentor Dr. Patricia D'Amore, scientific leader in the field of angiogenesis and retinal vascular diseases. The proposed research and career development plans will take place in the rich environments of Massa Eye and Ear and Harvard Medical School. The proposed research plan examines the direct relationship between blood vessels and nerves in the cornea. We have found that neurons isolated from the trigeminal ganglion, from which corneal nerves originate, directly inhibit vascular endothelial cell activities. In addition, neurons isolated from mice with ocular surface inflammation lose their anti-angiogenic function. Based on these data, we hypothesize that under normal conditions corneal nerves directly modulate angiogenesis via secreted neuropeptides, and that dysregulation of these neuropeptides after ocular surface inflammation promotes corneal neovascularization. Specifically, we propose that alpha-melanocyte-stimulating hormone, an immune-modulatory neuropeptide secreted by corneal nerves, contributes to the inhibition of angiogenesis under normal conditions (Aim 1). In addition, we propose that secretion of substance P, a key mediator of neurogenic inflammation, by corneal nerves is increased after acute ocular surface inflammation and this increase directly promotes corneal neovascularization (Aim 2). A unique and innovative in vitro co-culture system of trigeminal neurons and vascular endothelial cells will be used to examine these hypotheses in Aims 1 and 2. In Aim 3, we will use a suture-induced corneal neovascularization mouse model to determine the roles of these neuropeptides in vivo. The proposed research is of high relevance in ocular tissues and non-ocular settings characterized by peripheral nerve inflammation and degeneration. Successful completion of the proposal can lead to the development of therapeutics for corneal neovascularization and neuro-inflammation.