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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。

基本信息

批准号：
8857468
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
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-06-01 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8857468
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

项目摘要

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.

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。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Re: Kwon et al.: Aqueous levels of angiopoietin-like 4 and semaphorin 3E correlate with nonperfusion area and macular volume in diabetic retinopathy (Ophthalmology 2015;122:968-75).

回复：Kwon 等人：血管生成素样 4 和脑信号蛋白 3E 的水浓度与糖尿病视网膜病变的非灌注面积和黄斑体积相关（眼科 2015；122：968-75）。

DOI：
10.1016/j.ophtha.2015.05.023
发表时间：
2016
期刊：
Ophthalmology
影响因子：
13.7
作者：
Sodhi,Akrit;Montaner,Silvia
通讯作者：
Montaner,Silvia

Hypoxia promotes uveal melanoma invasion through enhanced Notch and MAPK activation.

缺氧通过增强的Notch和MAPK激活促进紫veal黑色素瘤的侵袭。

DOI：
10.1371/journal.pone.0105372
发表时间：
2014
期刊：
PloS one
影响因子：
3.7
作者：
Asnaghi L;Lin MH;Lim KS;Lim KJ;Tripathy A;Wendeborn M;Merbs SL;Handa JT;Sodhi A;Bar EE;Eberhart CG
通讯作者：
Eberhart CG

Angiopoietin-like 4 as an Emerging Therapeutic Target for Diabetic Eye Disease.

血管生成素样 4 作为糖尿病眼病的新兴治疗靶点。

DOI：
10.1001/jamaophthalmol.2015.3723
发表时间：
2015
期刊：
JAMA ophthalmology
影响因子：
8.1
作者：
Sodhi,Akrit;Montaner,Silvia
通讯作者：
Montaner,Silvia

Scleral penetration of an unusually aggressive case of a retinal hemangioblastoma.

异常侵袭性视网膜血管母细胞瘤病例的巩膜穿透。

DOI：
10.1016/j.jcjo.2013.01.014
发表时间：
2013
期刊：
Canadian journal of ophthalmology. Journal canadien d'ophtalmologie
影响因子：
0
作者：
Rodrigues,Murilo;Iliff,NicholasT;Eberhart,CharlesG;Montaner,Silvia;Sodhi,Akrit
通讯作者：
Sodhi,Akrit

Intraoperative optical coherence tomography demonstrates immediate closure of a traumatic macular hole.

术中光学相干断层扫描显示外伤性黄斑裂孔立即闭合。