Mechanisms of Neuroregulation of Corneal Angiogenesis

摘要(来自原始应用程序) 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 角膜疾病和眼睛免疫学的科学家，以及共同导师Patricia D‘Amore博士，科学领袖 血管生成和视网膜血管疾病领域。拟议的研究和职业发展计划 将在马萨眼耳和哈佛医学院的丰富环境中举行。建议数 研究计划检查角膜中血管和神经之间的直接关系。我们有 发现从产生角膜神经的三叉神经节分离出来的神经元直接抑制 血管内皮细胞活性。此外，从患有眼表炎症的小鼠身上分离的神经元 失去它们的抗血管生成功能。根据这些数据，我们假设在正常情况下，角膜 神经通过分泌的神经肽直接调节血管生成，而这些神经肽的失调 眼表炎症后的神经肽促进角膜新生血管形成。具体来说，我们建议 α-黑素细胞刺激素，一种由角膜神经分泌的免疫调节神经肽， 有助于在正常情况下抑制血管生成(目标1)。此外，我们建议 术后角膜神经分泌P物质增多，P物质是神经源性炎症的关键介质 急性眼表炎症，这种增加直接促进角膜新生血管(目标2)。一个 独特而创新的三叉神经细胞与血管内皮细胞体外共培养体系 用于检验目标1和目标2中的这些假设。在目标3中，我们将使用缝合诱导的角膜 建立小鼠新生血管模型，确定这些神经肽在体内的作用。拟议的研究 在以周围神经炎症为特征的眼部组织和非眼部环境中具有高度相关性 和退化。成功完成这项提议可以导致治疗的发展 角膜新生血管和神经炎症。

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.