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

HIF 失调作为研究视网膜新生血管疾病的新型遗传模型。

• 批准号: 8032771
• 负责人: Akrit Singh Sodhi
• 金额: $ 17.96万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8032771
• 关键词: Address; Age related macular degeneration; Area; Biochemical; Blindness; Blood Vessels; Blood-Retinal Barrier; Cell Communication; Cells; Clinical; Confocal Microscopy; Development; Disease; Edema; Etiology; Event; Eye; Eye Neoplasms; Family; Fluorescence Resonance Energy Transfer; Genes; Genetic Models; Goals; Growth; Growth Factor; Histopathology; Human; Hypoxia; Hypoxia Inducible Factor; Imaging Techniques; Ischemia; Lesion; Life; Macular degeneration; Mentors; Modeling; Molecular; Mus; Neovascular Glaucoma; Pathogenesis; Pathologic Neovascularization; Patients; Phenotype; Principal Investigator; Production; Proteins; Regulation; Relative (related person); Research; Research Personnel; Retina; Retinal; Retinal Artery Occlusion; Retinal Diseases; Retinal Neovascularization; Retinopathy of Prematurity; Role; Stimulus; Structure of central vein of the retina; Syndrome; Testing; Tissues; Training; Tumor Suppressor Genes; Up-Regulation; VHL protein; Vascular Endothelial Growth Factors; Vascular Permeabilities; Von Hippel-Lindau Syndrome; Work; angiogenesis; base; experience; hemangioblastoma; hypoxia inducible factor 1; in vivo; in vivo Model; insight; interest; neovascular; neovascularization; novel; overexpression; programs; proliferative diabetic retinopathy; protein complex; skills; transcription factor; tumor

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).

描述（由申请人提供）：该提案的总体目标是向主要研究人员（PI）提供成为研究视网膜新生血管疾病基本机制所必需的经验和技能。该提议的科学重点是更好地了解眼睛中病理血管生成的理解，这是全球不可逆失明的主要原因。新兴的证据表明，眼睛中的新血管化具有共同的病因，其中局部缺氧导致缺氧诱导因子（HIF）上调。 HIF是一个转录因子家族，刺激了几种“低氧诱导”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），进而促进（漏水）血管的生长。令人感兴趣的是，我们对HIF在病理血管生成中调节的理解的显着进展来自最近检查von Hippel-Lindau（VHL）疾病患者HIF的失调的工作。视网膜血管群是新生血管肿瘤，在VHL疾病患者中仍然是最常见的临床表现，通常表现出大量的水肿表现，并导致视力丧失。 VHL蛋白（PVHL）靶向HIF进行降解。因此，VHL疾病患者的PVHL丧失导致HIF的失调和低氧诱导基因的表达过度，模仿了病理血管生成。 该提议的基本假设是VHL视网膜血管群是病理血管生成的模型，并提供了一个理想的遗传模型，以检查HIF及其在内部血液视网膜屏障（IBRB）破裂（IBRB）中的作用，但在视网膜内部疾病中却很重要的早期事件。为了解决这一假设，提出了三个具体目标：目标1：检查IBRB崩溃时HIF的必要性。目标2：确定HIF失调是否足以促进IBRB的崩溃。目标3：确定IBRB崩溃中HIF依赖性生长因子的相对贡献。 在拟议的研究和选定的教学活动的过程中，PI将获得宝贵的训练经验，并在研究视网膜新血管疾病的分子发病机理方面获得指导。对于渴望制定独立研究计划的PI，该专业知识被认为是必不可少的，该计划研究了视网膜病理血管生成的基本机制。 公共卫生相关性：视网膜新血管疾病是发达国家不可逆失明的主要原因。该提案旨在研究潜在的细胞和生化变化，从而通过研究视网膜新生血管疾病的新遗传模型，从而导致内部血红素屏障的崩溃。除了多种视网膜疾病（例如增生性糖尿病性视网膜病，缺血性血管阻塞，早产性视网膜病和黄斑变性）外，这些研究可能会促进对其他眼部疾病的原因更大的欣赏，从而促进其他涉及非调节血管生成的异常血管生成的原因（例如，眼部肿瘤和内瘤瘤）。