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: 8242691
• 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/8242691
• 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; public health relevance; 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)：这项建议的总体目标是为首席研究员(PI)提供必要的经验和技能，以成为研究视网膜新生血管疾病基本机制的独立研究员。这项建议的科学重点是更好地了解眼睛中的病理性血管生成，这是全球不可逆转失明的主要原因。新的证据表明，眼部新生血管的共同病因是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，可以刺激几个“缺氧诱导”基因的产生，包括血管生成生长因子(如血管内皮生长因子或血管内皮生长因子)，后者反过来又促进(泄漏的)血管的生长。有趣的是，在我们理解HIF在病理性血管生成中的调节方面取得了重大进展，这是最近研究von Hippel-Lindau(VHL)病患者HIFs调节失调的工作取得的。视网膜血管母细胞瘤是一种新生血管肿瘤，是VHL病患者最常见的临床表现，通常表现为大量的水肿，导致严重的视力丧失。VHL蛋白(PVHL)针对HIF进行降解。因此，VHL患者pVHL的缺失导致HIFs的失调和低氧诱导基因的过度表达，类似于病理性的血管生成。这一提议的基本假设是，VHL视网膜血管母细胞瘤是病理性血管生成的模型，并提供了一个理想的遗传学模型来研究HIF及其靶点在视网膜内血视网膜屏障(IBRB)破坏中的作用(S)，这是一种知之甚少但在视网膜新生血管疾病中的关键早期事件。为了解决这一假设，提出了三个具体目标：目标1：检验高强度聚焦在iBRB崩溃中的必要性。目的2：确定缺氧诱导因子调节失调是否足以促进iBRB的崩溃。目的3：确定缺氧诱导因子依赖的生长因子在iBRB破裂中的相对贡献。在拟议的研究和选定的教学活动过程中，PI将在研究视网膜新生血管疾病的分子发病机制方面获得宝贵的培训经验和指导。这种专业知识被认为是PI的关键，他们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转失明的主要原因。这项建议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血-视网膜屏障破裂的潜在细胞和生化变化。除了众多的视网膜疾病(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)外，这些研究还可能促进对其他涉及血管生成失调的眼部疾病(如眼肿瘤和新生血管性青光眼)病因的更多认识。