Elucidation of the Regulation of Angiogenesis by Melanocytes in Age Related Macular Degeneration

阐明年龄相关性黄斑变性中黑素细胞对血管生成的调节

• 批准号: 10165717
• 负责人: Irit Adini
• 金额: $ 37.32万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10165717
• 关键词: Affect; African American; Age related macular degeneration; Angiogenic Factor; Animal Model; Asian Americans; Binding; Biological Assay; Birth; Blindness; Blood Vessels; Cellular Stress; Choroidal Neovascularization; Co-Immunoprecipitations; Disease; Endothelial Cells; Epidemiology; Equilibrium; Exudative age-related macular degeneration; Eye; Genetic; Goals; Growth; Human; Hypoxia; Immunofluorescence Microscopy; In Vitro; Incidence; Individual; Lasers; Measures; Mediating; Melanins; Melanogenesis; Modeling; Molecular; Monitor; Orphan; Outcome; Outcome Study; Oxidative Stress; Oxygen; Pathologic Neovascularization; Pathway interactions; Pharmacology; Physiological; Pigmentation physiologic function; Pigments; Prevalence; Process; Production; Race; Receptor Mediated Signal Transduction; Receptor Protein-Tyrosine Kinases; Regulation; Reporting; Retina; Retinal Diseases; Retinal Neovascularization; Risk; Role; Severities; Signal Transduction; Strawberry nevus; Testing; Therapeutic; UV Radiation Exposure; UV induced; Uveal Melanoma; Vascular Diseases; Western World; activating transcription factor; angiogenesis; cell injury; cell motility; cohort; epidemiology study; experimental study; fibromodulin; improved; in vivo; inhibitor/antagonist; insight; knock-down; melanocyte; mouse model; neovascularization; novel; overexpression; personalized medicine; prevent; prognostic; promoter; racial difference; receptor; receptor binding; tool; transcription factor; transcriptome sequencing

Project Abstract Angiogenesis, the formation of new blood vessels, is a regulated process determined by the local balance of endogenous stimulators versus inhibitors. Angiogenesis-dependent diseases are the major cause of blindness in the developed world. Epidemiological studies have shown that the incidence of exudative age-related macular degeneration (ARMD) is race dependent and highly correlated to pigmentation levels. Compared to white people, lowly-pigmented individuals, the prevalence of choroidal neovascularization is 55% lower in black people, highly-pigmented individuals and 46% lower in Asian Americans. The studies outlined in our proposal are aimed at understanding the role of melanocytes in ARMD. We have previously shown that melanocytes with low pigmentation have high expression levels of a novel angiogenic factor known as Fibromodulin (FMOD). We have confirmed FMOD's angiogenic activity in several in vivo angiogenesis models. The goal of this project is to elucidate the cellular mechanisms by which melanocytes induce pathological angiogenesis via FMOD. We now propose to: (1) Investigate the physiological conditions and molecular stimulators that increase FMOD expression by melanocytes, including identification of transcription factors that activate FMOD expression; (2) Investigate FMOD receptor-mediated signal transduction in angiogenesis by characterizing the FMOD - ROR2 interaction in endothelial cells; and (3) Establish how melanocytes promote angiogenesis via FMOD in various ocular animal models and human donor eyes. Understanding the role of melanocytes and melanocyte-secreted FMOD in vascular diseases would advance our understanding of the melanocytic microenvironment and offer novel targets for personalized treatment of angiogenesis-dependent diseases.

项目摘要 血管生成，即新血管的形成，是一个由以下因素决定的调节过程 内源性刺激因子与抑制因子的局部平衡。血管生成依赖 在发达国家，疾病是导致失明的主要原因。流行病学 研究表明，渗出性老年性黄斑变性的发病率 (ARMD)取决于种族，并与色素沉着水平高度相关。与.相比 白人、低色素个体、脉络膜的患病率 黑人、高色素人群的新生血管发生率低55%，高色素者低46% 亚裔美国人的比例较低。我们建议中概述的研究旨在 了解黑素细胞在ARMD中的作用。我们之前已经表明， 低色素沉着的黑素细胞高表达一种新的血管生成 称为纤维调素(FMOD)的因子。我们已经确认了FMOD的血管生成活性 在几个体内血管生成模型中。这个项目的目标是阐明细胞 黑素细胞通过FMOD诱导病理性血管生成的机制。我们 现建议：(1)研究生理条件和分子刺激物 增加黑素细胞FMOD的表达，包括转录鉴定 激活Fmod表达的因素；(2)研究Fmod受体介导的信号 FMOD-ROR2相互作用在血管生成中的转导作用 以及(3)确定黑素细胞如何通过FMOD促进血管生成。 各种眼部动物模型和人眼供体。了解企业的角色 血管疾病中的黑素细胞和黑素细胞分泌的FMOD将促进我们的 了解黑素细胞微环境并提供新的靶点 血管生成依赖型疾病的个性化治疗。