Mechanisms of Neuroregulation of Corneal Angiogenesis

角膜血管生成的神经调节机制

• 批准号: 10186760
• 负责人: Jia Yin
• 金额: $ 23.87万
• 依托单位: MASSACHUSETTS EYE AND EAR INFIRMARY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10186760
• 关键词: Acute; Advisory Committees; Angiogenesis Inhibition; Biological Process; Blood Vessels; Cell Proliferation; Chemical Burns; Clinical; Clinical Treatment; Coculture Techniques; Cornea; Corneal Diseases; Corneal Neovascularization; Data; Denervation; Development; Development Plans; Doctor of Medicine; Doctor of Philosophy; Ear; Environment; Exposure to; Eye; Genes; Goals; Homeostasis; Human body; Immune; Immunology; In Vitro; Inflammation; Inflammatory; Keratitis; Knockout Mice; Knowledge; Lead; Leadership; Maintenance; Massachusetts; Mediating; Mediator of activation protein; Mentors; Mus; Nerve; Nerve Degeneration; Neurogenic Inflammation; Neurons; Neuropeptides; Neurosciences; Ophthalmology; Pathologic; Peptides; Peripheral Nerves; Physiological; Pigmentation physiologic function; Play; Production; Program Development; Property; Public Health Schools; Research; Research Institute; Retina; Role; Scientific Advances and Accomplishments; Scientist; Sensory; Series; Signal Transduction; Small Interfering RNA; Stress; Structure of trigeminal ganglion; Substance P; Substance P Receptor; Surgical sutures; System; TACR1 gene; Techniques; Testing; Therapeutic; Tissues; Topical application; Training; Training Programs; Travel; Trigeminal System; Tube; Vascular Diseases; Vascular Endothelial Cell; Yin; adeno-associated viral vector; alpha-Melanocyte stimulating hormone; angiogenesis; base; blink reflexes; career; career development; corneal epithelial wound healing; experimental study; immunoregulation; in vitro activity; in vivo; innovation; knock-down; medical schools; meetings; migration; mouse model; neovascularization; neuroinflammation; neuroprotection; neuroregulation; novel; novel therapeutics; ocular surface; professor; research and development; skills; small hairpin RNA; stem cell niche; therapeutic development; wound healing

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.

该提案描述了一个为期 3 年的学术职业发展培训计划，重点关注 了解角膜血管生成的神经调节机制。候选人贾寅，医学博士， 哈佛医学院马萨诸塞州眼耳科医院眼科助理教授 她接受过角膜伤口愈合、血管生成和免疫学领域的科学培训，并且 尹博士的长期目标是促进角膜疾病的科学认识和发展。 致盲性角膜疾病的临床治疗 在这个三年职业发展计划中，她提出1) 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 资助，3) 通过课程、研讨会和会议培养领导和管理技能 顾问委员会包括著名临床医生 Reza Dana 博士。 角膜疾病和眼部免疫学科学家，联合导师 Patricia D'Amore 博士，该领域的科学领导者 血管生成和视网膜血管疾病领域的专家，合作者 Gabriel Corfas 博士是该领域的专家 拟议的研究和职业发展计划将包括神经科学和周围神经变性。 发生在马萨诸塞州 Schepens 眼科研究所丰富的环境中 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了血管和神经之间的直接关系 我们发现从三叉神经节中分离出神经元，其中角膜神经 此外，从小鼠眼部分离出神经元。 基于这些数据，我们在表面炎症失去了抗血管生成功能。 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，并且 眼表炎症后这些神经肽的失调会促进角膜新生血管形成。 具体来说，我们建议α-黑素细胞刺激激素，一种免疫调节神经肽 由角膜神经分泌，有助于在正常条件下抑制血管生成（目标 1）。 此外，我们认为角膜分泌 P 物质（神经源性炎症的关键介质） 急性眼表炎症后神经增加，这种增加直接促进角膜 新生血管形成（目标 2）。 血管内皮细胞将用于检验目标 1 和 2 中的这些假设。在目标 3 中，我们将使用 缝合诱导角膜新生血管形成小鼠模型以确定这些神经肽在体内的作用。 拟议的研究与眼组织和非眼环境具有高度相关性，其特征是 成功完成该提案可导致周围神经炎症和变性。 角膜新生血管和神经炎症治疗方法的开发。