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.

该建议描述了一个为期3年的培训计划，以开发专注于学术职业 了解角膜血管生成神经调节的机制。候选人Jia Yin，医学博士 博士是哈佛医疗 学校。她在角膜伤口愈合，血管生成和免疫学领域接受了科学训练，并且 角膜疾病的临床培训。 Yin博士的长期目标是提高科学理解和 盲目的角膜疾病的临床治疗。在这个为期三年的职业发展计划中，她提出TO 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） 授予技巧，以及3）通过课程，半手和会议发展领导力和管理技能 具有明确定义的里程碑。咨询委员会包括著名临床的导师Reza Dana博士 角膜疾病和眼部免疫学的科学家，同事Patricia D'Amore博士，科学领导者 血管生成和视网膜血管疾病领域，以及合作者Gabriel Corfas博士，专家 神经科学和周围神经变性。拟议的研究和职业发展计划将 发生在马萨诸塞州的Schepens Eye研究所的丰富环境中 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血管与神经之间的直接关系 角膜。我们发现从三叉神经节中分离出的神经元，角膜神经 起源于直接抑制血管内皮细胞活性。另外，从小鼠中分离的神经元 表面注射失去其抗血管生成功能。基于这些数据，我们假设 正常情况，角膜神经直接通过分泌的神经肽调节血管生成，并且 眼部感染后这些神经肽的失调会促进角膜新生血管化。 特别是，我们提出了α-螺旋细胞刺激的马龙，一种免疫调节性神经肽 由角膜神经分泌，有助于在正常条件下抑制血管生成（AIM 1）。在 另外，我们建议通过角膜的PERTANCE P的分泌P（神经源性感染的关键介体） 急性眼部感染后神经增加，这会增加直接促进角膜 新血管形成（AIM 2）。三叉神经元的独特而创新的体外共文化系统 血管内皮细胞将用于在AIM 1和2中检查这些假设。在AIM 3中，我们将使用一个 缝合诱导的角膜新血管化小鼠模型，以确定这些神经肽在体内的作用。 拟议的研究在眼组织和非目录环境中具有很高的相关性 周围神经感染和变性。该提案的成功完成可能会导致 开发用于角膜新生血管形成和神经炎症的治疗剂。