Regulation of CNS Angiogenesis By GPR124

GPR124 对 CNS 血管生成的调节

基本信息

批准号：
7428852
负责人：
CALVIN J KUO
金额：
$ 33.54万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-07-15 至 2010-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7428852
关键词：
Adenoviruses Adherens Junction Adult Alleles Anatomy Angiogenic Factor Angiogenic Switch Apoptosis Binding Biological Assay Biology Blood - brain barrier anatomy Blood Vessels Brain CNS processing Cell Communication Cells Chimeric Proteins Clinic Clinical Trials Colon Carcinoma Condition Data Defect Development Diabetic Retinopathy Disease Doctor of Medicine Doctor of Philosophy Embryo Embryonic Development Endothelial Cells Endothelium Extracellular Matrix Family Filopodia Genes Genetic Growth Hemorrhage Integrins Ischemia Knock-out Knockout Mice LacZ Genes Ligands Macular degeneration Malignant Neoplasms Mediator of activation protein Menstrual fluid Menstruation Microarray Analysis Molecular Monoclonal Antibodies Mus Myocardial Infarction Neuroglia Neurons Organism Paracrine Communication Pathologic Pathologic Processes Pericytes Peripheral Vascular Diseases Permeability Phase Phase III Clinical Trials Phenotype Physiological Physiological Processes Population Pregnancy Principal Investigator Process Protein Overexpression Receptor Protein-Tyrosine Kinases Regulation Renal Cell Carcinoma Reporter Genes Signal Transduction Stroke Structure Testing Tissues Tumor Angiogenesis Tumorigenicity Vascular Endothelial Growth Factor Receptor Vascular Endothelial Growth Factors Vascular Smooth Muscle Venous Wound Healing Yang aged angiogenesis cell type concept human GPRC5C protein insight mature animal member migration mutant neurovascular unit novel oncology programs response therapeutic angiogenesis therapeutic target tissue culture tumor

项目摘要

DESCRIPTION (provided by applicant): The neurovascular unit (NVU) consists of the brain endothelium, along with associated glia, pericytes and neurons. The molecular definition of mediators of cell-cell interaction between these cell types should yield significant insight into vascular function during physiologic and pathologic processes in the CNS. We have constructed a mouse knockout of GPR124, an orphan G-protein coupled receptor originally identified by its overexpression in tumor endothelium. Inactivation of GPR124 by replacement with a lacZ reporter gene results in embryonic lethality with hemorrhage which is strikingly restricted to the brain. Initial analysis of the mutant CNS microvasculature has revealed profound defects of angiogenic migration and sprouting, while expression analysis of GPR124 indicates expression is highly selective for CNS vasculature. The GPR124 phenotype is highly suggestive of defective paracrine signaling within cells of the neurovascular unit, resulting in improper angiogenesis. In the current proposal, the functions of GPR124 will be explored taking advantage of GPR124 knockout mice which we have created. First, the structure of aberrant vasculature in GPR124-/- mice will be studied with respect to qualitative and quantitative deficiencies of with other cells of the NVU, cellular junctions and extracellular matrix. Second, genetic epistatic relationships will be sought between GPR124 and other genes whose knockouts have similar phenotypes, such as integrins and Id transcriptional repressers. Third, cell types of the neurovascular unit, such as glia, pericytes and neurons, will be systematically tested for the ability to elicit GPR124-dependent responses in tissue culture. Finally, conditional approaches to GPR124 inactivation will be pursued using adenoviral and conditional knockout strategies, to facilitate the eventual study of GPR124 function in fully adult organisms.

描述（由申请人提供）：神经血管单元（NVU）由脑内皮以及相关的神经胶质细胞、周细胞和神经元组成。这些细胞类型之间的细胞-细胞相互作用介质的分子定义应该能够对中枢神经系统生理和病理过程中的血管功能产生重要的了解。我们构建了 GPR124 的小鼠敲除模型，GPR124 是一种孤儿 G 蛋白偶联受体，最初是通过其在肿瘤内皮细胞中的过度表达来识别的。通过替换 lacZ 报告基因来灭活 GPR124 会导致胚胎死亡并伴有出血，而出血仅限于大脑。对突变中枢神经系统微脉管系统的初步分析揭示了血管生成迁移和发芽的严重缺陷，而 GPR124 的表达分析表明表达对中枢神经系统脉管系统具有高度选择性。 GPR124 表型高度提示神经血管单元细胞内的旁分泌信号传导缺陷，导致血管生成不当。在当前的提案中，将利用我们创建的 GPR124 敲除小鼠来探索 GPR124 的功能。首先，将研究 GPR124-/- 小鼠中异常脉管系统结构与 NVU、细胞连接和细胞外基质的其他细胞的定性和定量缺陷。其次，将寻找 GPR124 和其他具有相似表型的敲除基因（例如整联蛋白和 Id 转录抑制子）之间的遗传上位关系。第三，神经血管单元的细胞类型，例如神经胶质细胞、周细胞和神经元，将系统地测试在组织培养中引发 GPR124 依赖性反应的能力。最后，将使用腺病毒和条件敲除策略来寻求 GPR124 失活的条件方法，以促进 GPR124 在完全成年生物体中的功能的最终研究。