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Mechanisms of Neuroregulation of Corneal Angiogenesis

角膜血管生成的神经调节机制

基本信息

批准号：
10649841
负责人：
Jia Yin
金额：
$ 5.4万
依托单位：
MASSACHUSETTS EYE AND EAR INFIRMARY
依托单位国家：
美国
项目类别：
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/10649841
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 Neurogenic Inflammation Neurons Neuropeptides Neurosciences Ophthalmology Pathologic Peptides Peripheral Nerves Physiological Pigmentation physiologic function Play Production Program Development Property Research 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 antagonist 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

项目摘要

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.

摘要（来自原始申请）该提案描述了一个为期3年的培训计划，以发展学术生涯为重点，了解角膜血管生成的神经调节机制。候选人贾寅博士，博士是马萨诸塞州眼耳医院、哈佛医学院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。尹博士的长期目标是推进科学认识，致盲性角膜疾病的临床治疗。在这份3年职业发展规划中，她提出1）提高神经科学、血管生成和免疫学方面的科学知识和技术，2）磨练通过课程、研讨会和会议，培养领导和管理技能有明确的里程碑。顾问委员会包括导师Reza Dana博士，著名的临床医生角膜疾病和眼部免疫学的科学家，以及共同导师Patricia D 'Amore博士，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进行。拟议研究计划探讨角膜血管和神经之间的直接关系。我们有发现从三叉神经节分离的神经元，角膜神经起源，直接抑制血管内皮细胞活性。此外，从患有眼表炎症的小鼠中分离的神经元失去了抗血管生成的功能。基于这些数据，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，眼表炎症后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，有助于在正常条件下抑制血管生成（目的1）。此外，我们建议，角膜神经分泌的P物质（神经源性炎症的关键介质）在急性眼表炎症，这种增加直接促进角膜新生血管形成（目的2）。一独特和创新的三叉神经神经元和血管内皮细胞的体外共培养系统将是用于检验目标1和2中的这些假设。在目标3中，我们将使用缝线诱导角膜新血管形成小鼠模型以确定这些神经肽在体内的作用。拟议研究在眼组织和以周围神经炎症为特征的非眼环境中具有高度相关性和退化该提案的成功完成可以导致治疗方法的发展，角膜新生血管和神经炎症。