HIF dysregulation as a novel genetic model to study retinal neovascular disease.

描述（由申请人提供）：本提案的总体目标是为主要研究者（PI）提供必要的经验和技能，使其成为研究视网膜新生血管疾病基本机制的独立研究者。该提案的科学重点是更好地了解眼睛中的病理性血管生成，这是全球不可逆失明的主要原因。新出现的证据表明，局部缺氧导致缺氧诱导因子（HIF）上调的眼部新生血管形成的共同病因。HIF是一个转录因子家族，其刺激几种“缺氧诱导型”基因的产生，包括血管生成生长因子（例如血管内皮生长因子或VEGF），其进而促进（渗漏）血管的生长。有趣的是，我们对HIF在病理性血管生成中的调节的理解的重大进展来自于最近的研究von Hippel-Lindau（VHL）病患者中HIF调节异常的工作。视网膜血管母细胞瘤是新生血管性肿瘤，仍然是VHL疾病患者最常见的临床表现，通常表现为大量水肿并导致严重的视力丧失。VHL蛋白（pVHL）靶向HIF进行降解。因此，VHL疾病患者中pVHL的缺失导致HIF的失调和缺氧诱导基因的过度表达，模拟病理性血管生成。 该提议的基本假设是VHL视网膜成血管细胞瘤是病理性血管生成的模型，并提供了理想的遗传模型来检查HIF及其靶标在内部血-视网膜屏障（iBRB）破坏中的作用，iBRB是视网膜新生血管疾病中理解不多但关键的早期事件。为了解决这一假设，提出了三个具体的目标：目标1：研究在iBRB的故障的HIF的必要性。目的2：确定HIF失调是否足以促进iBRB的破坏。目的3：确定HIF依赖性生长因子在iBRB分解中的相对贡献。 在拟议的研究和选定的教学活动的过程中，PI将获得宝贵的培训经验和指导，在研究视网膜新生血管疾病的分子发病机制。这种专业知识被认为是必不可少的PI谁渴望开发一个独立的研究计划，研究视网膜病理性血管生成的基本机制。 公共卫生相关性：视网膜新生血管疾病是发达国家不可逆失明的主要原因。该提案旨在通过研究视网膜新生血管疾病的新遗传模型来研究导致内部血液-视网膜屏障破裂的潜在细胞和生化变化。除了许多视网膜疾病（例如，增殖性糖尿病视网膜病变、缺血性血管闭塞、早产儿视网膜病变和黄斑变性）之外，这些研究可能促进对涉及血管生成失调的其他眼部疾病（例如，眼部肿瘤和新生血管性青光眼）的病因的更高认识。

DESCRIPTION (provided by applicant): The overall goal of this proposal is to provide the principal investigator (PI) with the experience and skills necessary to become an independent researcher studying basic mechanisms of retinal neovascular disease. The scientific focus of this proposal is to gain a better understanding of pathological angiogenesis in the eye, a principal cause of irreversible blindness worldwide. Emerging evidence suggests a shared etiology for neovascularization in the eye in which local hypoxia leads to upregulation of the hypoxia inducible factor (HIFs). HIFs are a family of transcription factors which stimulate production of several "hypoxia inducible" genes, including angiogenic growth factors (e.g. vascular endothelial growth factor or VEGF), which, in turn, promote the growth of (leaky) blood vessels. Of interest, significant progress in our understanding of the regulation of HIFs in pathological angiogenesis has come from recent work examining the dysregulation of HIFs in patients with von Hippel-Lindau (VHL) disease. Retinal hemangioblastomas are neovascular tumors that remain the most common clinical manifestation in patients with VHL disease, often manifesting with profuse edema and resulting in profound loss of vision. The VHL protein (pVHL) targets HIFs for degradation. Therefore, loss of pVHL in patients with VHL disease results in dysregulation of HIFs and over expression of hypoxia-inducible genes, mimicking pathological angiogenesis. The underlying hypothesis of this proposal is that VHL retinal hemangioblastomas are a model for pathological angiogenesis and provide an ideal genetic model to examine the role(s) of HIFs and their targets in the breakdown of the inner blood- retinal barrier (iBRB), a poorly understood, but critical early event in retinal neovascular disease. To address this hypothesis, three specific aims are proposed: Aim 1: To examine the necessity for HIFs in the breakdown of the iBRB. Aim 2: To determine if HIF dysregulation is sufficient to promote breakdown of the iBRB. Aim 3: To determine the relative contribution of HIF-dependent growth factors in breakdown of the iBRB. In the course of the proposed research and selected didactic activities, the PI will gain invaluable training experience and mentoring in studying the molecular pathogenesis of retinal neovascular disease. This expertise is deemed essential for the PI who aspires to develop an independent research program studying basic mechanisms of retinal pathological angiogenesis. PUBLIC HEALTH RELEVANCE: Retinal neovascular disease is the leading cause of irreversible blindness in the developed world. This proposal intends to study the underlying cellular and biochemical changes leading to the breakdown of the inner blood-retinal barrier by studying a novel genetic model for retinal neovascular disease. In addition to numerous retinal diseases (e.g. proliferative diabetic retinopathy, ischemic vascular occlusions, retinopathy of prematurity, and macular degeneration), these studies may promote a greater appreciation for the cause of other ocular diseases which involve dysregulated angiogenesis (e.g. ocular tumors and neovascular glaucoma).