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（由申请人提供）：在理解病理视网膜血管生成的机制时，我们发现除了VEGFA，VEGFA，VEGFB，VEGFC，DLL4和裂解Notch1诱导外，缺氧还以强大的和持续的方式激活小鼠视网膜中的CREB和STAT3。有趣的是，CREB或STAT3的阻塞抑制了VEGFC和FGF2诱导的DLL4表达，并在HRMVEC中裂解Notch1。大量研究表明，通过调节尖端与茎细胞分化的凹槽信号传导在发育和产后血管生成中起关键作用。 CREB属于转录因子的基本/亮氨酸拉链（BZIP）家族，并且具有结合o共识序列TGAC/GTCA的能力，在基因的启动子区域中，可以增强其表达，以响应各种刺激剂，包括细胞因子，生长因子和激素，并参与神经元塑料的调节，涉及细胞因子，生长因子和长期塑料的调节。同样，STAT3属于转录因子家族，其活性受Tyr/Ser磷酸化和乙酰化的调节，具有与共识序列TTCCGGGAA结合的能力，在基因的启动子区域中，诱导其表达的基因表达，以响应大量的刺激物，包括细胞因子和迁移因子和迁移因子和轮廓。虽然大量数据证明了这些转录因子在调节许多细胞过程中的重要性，包括细胞增殖，迁移和分化，但实际上却没有任何知识在病理视网膜血管生成中的作用，特别是与Notch信号有关。基于我们新颖的初步观察，我们假设CREB和STAT3通过增强DLL4的表达，从而介导了病理视网膜新生血管形成。为了解决这一假设，我们将测试以下三个特定目的：目标1。测试CREB介导缺氧诱导的病理视网膜新血管形成的假设。目的2。测试STAT3介导缺氧诱导的视网膜新血管形成的假设。目的3。为了测试以下假设：缺氧通过CREB和STAT3诱导DLL4-NOTCH1信号传导，从而导致漏水和非模式性病理性视网膜新生血管化。本赠款应用中提出的实验的执行应为我们提供有关介导病理视网膜新血管形成中Notch信号激活上游机制的新信息，并且这种知识将有助于针对这种衰弱的眼部疾病的治疗药物开发。