Mechanisms of Neuroregulation of Corneal Angiogenesis

这项建议描述了一个为期3年的学术生涯发展培训计划，重点是 了解角膜血管生成的神经调节机制。候选人贾茵，医学博士， 博士是哈佛医学院马萨诸塞州眼耳医院眼科学助理教授 学校。她在角膜伤口愈合、血管生成和免疫学领域接受过科学培训， 角膜疾病的临床培训。殷博士的长期目标是推动对科学的理解和 致盲角膜疾病的临床治疗。在这份为期3年的职业发展计划中，她建议 增强神经科学、血管生成和免疫学方面的科学知识和技术，2)磨练 3)通过课程、研讨会和会议发展领导力和管理技能 具有明确定义的里程碑。顾问委员会包括著名临床医生Reza Dana博士的导师 角膜疾病和眼免疫学科学家，共同导师Patricia D‘Amore博士，科学领袖 和合作者Gabriel Corfas博士，他是 神经科学和周围神经退行性变。拟议的研究和职业发展计划将 在马萨诸塞州谢彭斯眼科研究所丰富的环境中举行 医务室、哈佛医学院和哈佛公共卫生学院。 拟议的研究计划检查血管和神经之间的直接关系。 眼角膜。我们发现，从三叉神经节分离出的神经元，角膜神经 产生、直接抑制血管内皮细胞活性。此外，从小鼠眼部分离的神经元 表面炎症失去了抗血管生成的功能。根据这些数据，我们假设在 正常情况下，角膜神经通过分泌神经肽直接调节血管生成，并且 眼表炎症后这些神经肽的失调促进了角膜新生血管的形成。 具体地说，我们建议阿尔法-黑素细胞刺激素，一种免疫调节神经肽 由角膜神经分泌，在正常情况下有助于抑制血管生成(目标1)。在……里面 此外，我们认为，P物质的分泌，神经源性炎症的关键介质，通过角膜 急性眼表炎症后神经增加，这种增加直接促进角膜 新生血管(目标2)。一种独特而创新的三叉神经细胞体外共培养体系 血管内皮细胞将在目标1和目标2中用于检验这些假设。在目标3中，我们将使用 用缝线诱导的小鼠角膜新生血管模型，确定这些神经肽在体内的作用。 建议的研究在眼组织和非眼组织中具有很高的相关性，其特征是 周围神经炎症和变性。成功完成该提案可导致 角膜新生血管和神经性炎症的治疗进展。

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, co-mentor Dr. Patricia D'Amore, scientific leader in the field of angiogenesis and retinal vascular diseases, and collaborator Dr. Gabriel Corfas, an expert in neuroscience and peripheral nerve degeneration. The proposed research and career development plans will take place in the rich environments of Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Harvard Medical School, and Harvard School of Public Health. 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.