Mechanisms of retinal angiogenesis

视网膜血管生成机制

基本信息

批准号：
8453956
负责人：
GADIPARTHI N RAO
金额：
$ 37.5万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-06-01 至 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8453956
关键词：
Abbreviations Acetylation Address Age related macular degeneration Applications Grants Binding Blindness Blood Vessels CREB1 gene Cell Differentiation process Cell Proliferation Cell physiology Cleaved cell Consensus Sequence Cyclic AMP-Responsive DNA-Binding Protein Data Development Disease Dominant-Negative Mutation EP300 gene Endothelial Cells FGF2 gene Family Fibroblast Growth Factor 2 Funding Genes Growth Growth Factor Hemorrhage Human Hypoxia Knowledge Ligands Mediating Metabolism MicroRNAs Mitogen-Activated Protein Kinases Mus NOTCH1 gene Neuronal Plasticity Pattern Pharmaceutical Preparations Phosphorylation Placental Growth Factor Play Promoter Regions Protein Kinase C Regulation Retina Retinal Retinal Diseases Retinal Neovascularization Role STAT3 gene Signal Transduction Small Interfering RNA Somatotropin Stat3 protein Testing Therapeutic Time Study Tube VEGFA gene VEGFC gene Vascular Endothelial Growth Factor A Vascular Endothelial Growth Factor Receptor-1 Vascular Permeabilities angiogenesis antiangiogenesis therapy bZIP Domain base cell growth cell motility cytokine glucosylthiazolidine-4-carboxylic acid long term memory migration novel postnatal public health relevance research study response retinal angiogenesis small hairpin RNA src-Family Kinases therapeutic development

项目摘要

DESCRIPTION (provided by applicant): In understanding the mechanisms of pathological retinal angiogenesis, we have discovered that besides VEGFA, VEGFB, VEGFC, DLL4 and cleaved NOTCH1 induction, hypoxia activates CREB and STAT3 in the mouse retina in a robust and sustained manner. Interestingly enough, blockade of either CREB or STAT3 inhibits VEGFC and FGF2-induced expression of DLL4 and cleaved NOTCH1 in HRMVECs. A large number of studies suggest that NOTCH signaling by modulating the tip versus stalk cell differentiation plays a pivotal role in developmental and postnatal angiogenesis. CREB belongs to a basic/leucine zipper (bZIP) family of transcriptional factors and possess the ability to bind o the consensus sequence TGAC/GTCA in the promoter regions of genes enhancing their expression in response to a wide variety of stimulants, including cytokines, growth factors and hormones and is involved in the regulation of neuronal plasticity, long-term memory and cellular metabolism. Similarly, STAT3, which belongs to a family of transcriptional factors and whose activity is regulated by Tyr/Ser phosphorylation and acetylation, possess the ability to bind to th consensus sequence TTCCGGGAA in the promoter regions of genes inducing their expression in response to a large spectrum of stimulants, including cytokines, growth factors and hormones and is involved in the modulation of cellular growth and migration. While a large body of data demonstrates the importance of these transcriptional factors in the regulation of many cellular processes, including cell proliferation, migration and differentiation, literally nothing is known n regard to their role in the regulation of pathological retinal angiogenesis, particularly in concer with NOTCH signaling. Based on our novel preliminary observations, we hypothesize that CREB and STAT3 via enhancing the expression of DLL4 and thereby NOTCH1 signaling mediates pathological retinal neovascularization. To address this hypothesis, we will test the following three specific aims: Aim 1. To test the hypothesis that CREB mediates hypoxia-induced pathological retinal neovascularization. Aim 2. To test the hypothesis that STAT3 mediates hypoxia-induced pathological retinal neovascularization. Aim 3. To test the hypothesis that hypoxia induces DLL4-NOTCH1 signaling via CREB and STAT3 leading to leaky and non- patterning pathological retinal neovascularization. The execution of the experiments proposed in this grant application should provide us novel information on the upstream mechanisms of NOTCH signaling activation in mediating pathological retinal neovascularization and such knowledge would be useful in the development of therapeutic drugs against this debilitating ocular disease.

描述（申请人提供）：在了解病理性视网膜血管生成的机制时，我们发现除了 VEGFA、VEGFB、VEGFC、DLL4 和 cleaved NOTCH1 诱导外，缺氧还以强健且持续的方式激活小鼠视网膜中的 CREB 和 STAT3。有趣的是，阻断 CREB 或 STAT3 都会抑制 HRMVEC 中 VEGFC 和 FGF2 诱导的 DLL4 和切割的 NOTCH1 的表达。大量研究表明，NOTCH 信号通过调节尖端细胞与茎细胞的分化，在发育和出生后血管生成中发挥着关键作用。 CREB 属于转录因子的碱性/亮氨酸拉链 (bZIP) 家族，具有与基因启动子区域的共有序列 TGAC/GTCA 结合的能力，增强其表达以响应多种刺激物，包括细胞因子、生长因子和激素，参与神经元可塑性、长期记忆和细胞代谢的调节。同样，STAT3 属于转录因子家族，其活性受 Tyr/Ser 磷酸化和乙酰化调节，具有与基因启动子区域的共有序列 TTCCGGGAA 结合的能力，诱导其表达以响应大谱兴奋剂，包括细胞因子、生长因子和激素，参与细胞生长和迁移的调节。虽然大量数据表明这些转录因子在调节许多细胞过程（包括细胞增殖、迁移和分化）中的重要性，但实际上对其在调节病理性视网膜血管生成中的作用一无所知，特别是与NOTCH 信号。基于我们新的初步观察，我们假设 CREB 和 STAT3 通过增强 DLL4 的表达，从而 NOTCH1 信号传导介导病理性视网膜新生血管形成。为了解决这个假设，我们将测试以下三个具体目标：目标 1. 测试 CREB 介导缺氧诱导的病理性视网膜新生血管的假设。目标 2. 检验 STAT3 介导缺氧诱导的病理性视网膜新生血管形成的假设。目标 3. 检验缺氧通过 CREB 和 STAT3 诱导 DLL4-NOTCH1 信号传导导致渗漏和非模式化病理性视网膜新生血管形成的假设。本拨款申请中提出的实验的执行应该为我们提供有关 NOTCH 信号激活在介导病理性视网膜新生血管中的上游机制的新信息，并且这些知识将有助于开发针对这种使人衰弱的眼部疾病的治疗药物。