Molecular Mechanisms of Arterigenesis

动脉发生的分子机制

基本信息

批准号：
8424224
负责人：
Michael Simons
金额：
$ 180.54万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-02-10 至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8424224
关键词：
Adult Arteries Blood Circulation Blood Vessels Cardiology Cardiovascular Diseases Cardiovascular system Cellular biology Cerebrovascular Disorders Clinical Coronary Arteriosclerosis Defect Development Diabetes Mellitus Disease Ephrins Equilibrium Event Extracellular Matrix Failure Goals Growth Growth and Development function Instruction Lead Mechanics Mediator of activation protein Modality Molecular Molecular Biology Morbidity - disease rate Neuropilin-1 Nitric Oxide Pathology Peripheral arterial disease Pharmacology Process Role Signal Pathway Signal Transduction Structure Therapeutic Tunica Adventitia Vascular Endothelial Growth Factor Receptor-2 Vascular Endothelial Growth Factors base biomechanical engineering combat human FRAP1 protein hypercholesterolemia mortality multidisciplinary novel novel therapeutic intervention novel therapeutics programs receptor shear stress

项目摘要

DESCRIPTION (provided by applicant): Arteriogenesis is the process of formation of new arterial blood vessels during development or in the adult circulation. In development it entails formation of new endothelial vascular structures with arterial identity as defined by expression of key markers such ephrin 82 and neuropilin 1 followed by acquisition of the media and adventitia. In the adult circulation new arteries arise either by expansion of the pre-existing arterial vascular structures or de novo. Deletion of VEGF, its receptor VEGFR2 or key intracellular signaling mediators results in failure of arterial vasculature development. Defective arteriogenesis is noted in other setting including deletion of eNOS or in disease states such as diabetes and hypercholesterolemia and this failure contributes greatly to morbidity and mortality associated with these diseases. Nevertheless, the entire process is little understood and there are no currently successful approaches to deal with its defects in clinical settings. Understanding of molecular mechanism regulating arteriogenesis would be of great benefit to our understanding of pathobiology of major cardiovascular illnesses and to the development of new therapeutic approaches to combat them. In this PPG we propose a comprehensive approach to investigate the molecular basis of arteriogenesis and to develop new intellectual framework for therapeutic advances in this field. To this end, we will investigate a novel signaling pathway that seems to be critical to arteriogenesis (Project 1), study contributions of nitric oxide and the extracellular matrix (Project 2), evaluate the central role of mTOR in balancing various arteriogenic signaling inputs (Project 3) and determine the role of shear stress and other mechanical factors in initiating arteriogenesis in ad

描述（由申请人提供）：动脉生成是在发育过程中或在成人循环中形成新动脉血管的过程。在发育过程中，它需要形成具有动脉特性的新内皮血管结构，其定义是通过关键标记物（如肝配蛋白 82 和神经毡蛋白 1）的表达来定义，然后获得中膜和外膜。在成人循环中，新动脉要么通过先前存在的动脉血管结构的扩张而产生，要么从头产生。 VEGF、其受体 VEGFR2 或关键细胞内信号传导介质的缺失会导致动脉血管系统发育失败。在其他情况下，包括 eNOS 缺失或在糖尿病和高胆固醇血症等疾病状态下，也注意到动脉生成缺陷，这种失败极大地增加了与这些疾病相关的发病率和死亡率。然而，人们对整个过程知之甚少，目前还没有成功的方法来解决临床环境中的缺陷。了解调节动脉生成的分子机制将有助于我们了解主要心血管疾病的病理学以及开发新的治疗方法来对抗这些疾病。在本 PPG 中，我们提出了一种综合方法来研究动脉生成的分子基础，并为该领域的治疗进展开发新的知识框架。为此，我们将研究一种似乎对动脉生成至关重要的新信号通路（项目 1），研究一氧化氮和细胞外基质的贡献（项目 2），评估 mTOR 在平衡各种动脉生成信号输入中的核心作用（项目 3) 并确定剪切应力和其他机械因素在启动动脉生成中的作用