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

项目摘要 血管生成，即新血管的形成，是一个受调节的过程，由 内源性刺激物与抑制物的局部平衡。血管生成依赖性 疾病是发达国家失明的主要原因。流行病学 研究表明渗出性老年性黄斑变性的发病率 （ARMD）是种族依赖性的，与色素沉着水平高度相关。相比 白色人，低色素个体，脉络膜的患病率 新生血管在黑人、高色素个体中低55%，在高色素个体中低46%。 在亚裔美国人中更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。我们之前已经证明， 低色素沉着的黑素细胞具有高表达水平的新的血管生成因子， 纤维调节蛋白（Fibromodulin，FMOD）我们已经证实了FMOD的血管生成活性 在几种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 现提出：（1）研究生理条件和分子刺激物 增加黑素细胞的FMOD表达，包括鉴定转录 激活FMOD表达的因子;（2）研究FMOD受体介导的信号 通过表征FMOD-ROR 2在血管生成中的相互作用， 内皮细胞;和（3）建立黑素细胞如何通过FMOD促进血管生成， 各种眼部动物模型和人类供体眼睛。理解的作用 血管疾病中的黑素细胞和黑素细胞分泌的FMOD将促进我们的研究。 了解黑素细胞微环境，并提供新的目标， 血管生成依赖性疾病的个性化治疗。

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.