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: 8650284
• 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: 2011-06-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8650284
• 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）：本提案的总体目标是为主要研究者（PI）提供成为研究视网膜新生血管疾病基本机制的独立研究者所需的经验和技能。该提案的科学重点是更好地了解眼睛的病理性血管生成，这是全世界不可逆转失明的主要原因。新出现的证据表明，眼部新生血管形成有一个共同的病因，即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，可刺激多种“缺氧诱导”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（渗漏）血管的生长。有趣的是，最近对 von Hippel-Lindau (VHL) 疾病患者 HIF 失调的研究，使我们对 HIF 在病理性血管生成中的调节的理解取得了重大进展。视网膜血管母细胞瘤是新生血管肿瘤，仍然是 VHL 疾病患者最常见的临床表现，通常表现为严重水肿并导致视力严重丧失。 VHL 蛋白 (pVHL) 以 HIF 为目标进行降解。因此，VHL 疾病患者 pVHL 的缺失会导致 HIF 失调和缺氧诱导基因过度表达，类似于病理性血管生成。 该提案的基本假设是，VHL 视网膜血管母细胞瘤是病理性血管生成的模型，并提供理想的遗传模型来检查 HIF 及其靶点在血视网膜内屏障 (iBRB) 破坏中的作用，a视网膜新生血管疾病的了解甚少，但至关重要的早期事件。为了解决这一假设，提出了三个具体目标： 目标 1：检验 HIF 在 iBRB 分解中的必要性。目标 2：确定 HIF 失调是否足以促进 iBRB 崩溃。目标 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。这种专业知识对于希望​​开发研究视网膜病理性血管生成基本机制的独立研究项目的 PI 来说至关重要。 公共卫生相关性：视网膜新生血管疾病是发达国家不可逆性失明的主要原因。该提案旨在通过研究视网膜新生血管疾病的新型遗传模型来研究导致内部血视网膜屏障破坏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，这些研究可能会促进人们更好地了解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） ）。