Molecular mechanisms of choroidal neovascularization and vascular homeostasis

描述(申请人提供)：老年性黄斑变性(AMD)中的脉络膜新生血管(CNV)是世界范围内导致失明的主要原因之一。我们的长期目标是阐明调控脉络膜血管发育、成人脉络膜血管动态平衡和CNV的分子机制。了解这些机制可能会为新生血管性AMD患者的更有针对性的治疗方法提供基础。最近的实验和临床数据为血管内皮生长因子信号在CNV中的致病作用提供了强有力的证据。抗血管内皮生长因子治疗在减少新生血管性AMD患者的CNV方面显示出临床上的好处。然而，血管内皮生长因子刺激眼睛CNV的分子机制还知之甚少。我们提出的实验旨在全面分析血管内皮生长因子及其受体Flt1和Flk1在脉络膜血管功能中的单独作用，并探索这些信号通路作为新的治疗方法治疗新生血管性AMD的分子靶点。为此，我们将在小鼠身上进行结合使用条件性基因打靶方法和封闭抗体治疗的实验。我们将测试血管内皮生长因子、Flt1和Flk1在脉络膜内皮细胞功能中的作用。此外，我们将使用建立的小鼠CNV实验模型来研究血管内皮生长因子及其受体在CNV中的作用。此外，我们还将进行GFP阳性的骨髓移植实验和巨噬细胞耗竭实验，以确定实验性CNV病变的细胞组成，并在该模型中研究靶向血管内皮生长因子信号通路的抗体对这些细胞的影响。公共卫生相关性：老年性黄斑变性中的脉络膜新生血管是世界范围内导致失明的主要原因之一，但对导致眼睛中这种异常新生血管的分子机制知之甚少。本研究的目的是探讨血管内皮生长因子信号在脉络膜血管的发育、血管内稳态和病理性新生血管中的作用。这些发现可能为治疗新生血管性老年性黄斑变性提供新的分子靶点。

DESCRIPTION (provided by applicant): Choroidal neovascularization (CNV) in age-related macular degeneration (AMD) is one of the leading causes of blindness worldwide. Our long-term goal is to elucidate the molecular mechanisms that regulate choroidal vascular development, choroidal vascular homeostasis in the adult, and CNV. Understanding these mechanisms is likely to provide the basis for a more targeted therapeutic approach in patients with neovascular AMD. Recent experimental and clinical data have provided strong evidence for a pathogenetic role of VEGF signaling in CNV. Anti-VEGF treatments have shown clinical benefit in reducing CNV in patients with neovascular AMD. However, the molecular mechanisms through which VEGF stimulates CNV in the eye are only poorly understood. Our proposed experiments are directed towards a comprehensive analysis of the individual contributions of VEGF and the VEGF-receptors Flt1 and Flk1 for choroidal vascular functions, and towards exploring these signaling pathways as molecular targets for novel therapeutic approaches in the treatment of neovascular AMD. For this purpose, we will perform experiments that use a combination of conditional gene targeting approaches and treatments with blocking antibodies in mice. We will test the role of VEGF, Flt1 and Flk1 for choroidal endothelial cell functions. Furthermore, we will use an established experimental model for CNV in mice to investigate the role of VEGF and its receptors for CNV. In addition, we will perform GFP-positive bone marrow transplantation experiments and macrophage depletion experiments in order to determine the cellular composition of experimental CNV lesions and to study the effect of antibodies that target VEGF signaling pathways on these cells in this model. PUBLIC HEALTH RELEVANCE: Choroidal neovascularization in age-related macular degeneration is one of the leading causes of blindness worldwide, but only little is known about the molecular mechanisms that result in this abnormal neovascularization in the eye. The goal of the proposed studies is to investigate the role of VEGF signaling for the development, vascular homeostasis and pathological neovascularization of the choroidal vasculature. These findings are likely to reveal novel molecular targets for the treatment of neovascular age-related macular degeneration.