Role of integrin a5 in the development of aortic arch arteries.

整合素 a5 在主动脉弓动脉发育中的作用。

• 批准号: 8091073
• 负责人: Sophie Astrof
• 金额: $ 33.58万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8091073
• 关键词: Address; Aortic Arch Branch; Arteries; Cardiac; Data; Defect; Development; Developmental Process; DiGeorge Syndrome; Down-Regulation; Embryo; Endothelium; Etiology; India ink stain; Integrins; Molecular; Pattern Formation; Process; Role; Smooth Muscle Myocytes; aortic arch; congenital heart disorder; prevent

Congenital heart disease is the leading cause of infant mortality and morbidity in the developed world. The outflow vasculature of the heart is composed of aorta, pulmonary artery and a system of aortic arch arteries (AAAs) - proper development of this system is essential for the separation of venous and oxygenated blood and is required for human viability and health. Abnormal patterning of aortic arch arteries gives rise to severe birth defects and often occurs as a part of other congenital syndromes such as DiGeorge syndrome, one of the most common chromosome microdeletion syndromes in humans (1 in 4000 live births). Our long-term goal is to understand molecular and genetic pathways mediating normal AAA development in order to gain insight into the processes that go awry during pathological morphogenesis of the AAAs. Experiments in my laboratory led to the discovery that expression of integrin a5 in Isl1-positive cells and their descendants is required for the development of the aortic arch. We also found that integrin a5 is required for the presence of normal numbers of cardiac neural crest (CNC) cells in the pharyngeal arches. Since CNC cells give rise to vascular smooth muscle cells (VSMCs) of the AAAs and since normal formation, recruitment and association of VSMCs with aortic arch artery endothelial cells is required for the proper patterning of the AAAs, we propose to find out the role of integrin a5 in the development of the CNC cells and its descendants, VSMCs. Our specific aims will address three important questions about the function of integrin a5: a) what is the general role of integrin a5 in CNC development; b) how does the expression of integrin a5 in non-CNC cells affect the development of CNC and its derivatives; c) is integrin a5 required to facilitate growth factor signaling in the relevant pharyngeal arch cell types. To address these questions we propose the following three specific aims: I) To test the hypothesis that Itga5 is required to regulate survival and proliferation of the CNC progenitors; II) To test the hypothesis that expression of Itga5 in non-CNC cells is required for the formation and/or remodeling of AAAs; III) To determine the cellular and molecular mechanisms of Itga5 function during AAA development. Upon completion of this project, we will gain a significant insight into the function of integrin a5 in AAA development and into the normal process of AAA morphogenesis.

先天性心脏病是发达国家婴儿死亡率和发病率的主要原因。心脏的流出脉管系统由主动脉，肺动脉和主动脉弓动脉系统（AAAS）组成 - 该系统的正确发展对于分离静脉和含氧血液至关重要，对于人类的生存能力和健康是必需的。主动脉弓动脉的异常模式会导致严重的先天缺陷，并且通常是其他先天性综合征的一部分，例如Digeorge综合征，Digeorge综合征是人类中最常见的染色体微骨骼综合征之一（4000分之1中的1分）。我们的长期目标是了解介导正常AAA发育的分子和遗传途径，以深入了解在AAA的病理形态发生过程中出现问题的过程。我的实验室中的实验导致发现，ISL1阳性细胞中整联蛋白A5的表达及其后代是主动脉弓的发展所必需的。我们还发现，咽弓中存在正常数量的心脏神经rest（CNC）细胞所必需的整联蛋白A5。由于CNC细胞会引起AAAS的血管平滑肌细胞（VSMC），并且由于正常形成，因此VSMC与主动脉弓动脉内皮细胞的募集和关联是AAAS的适当构图所必需的，因此我们建议找出整联蛋白A5在CNC细胞开发中的作用。我们的具体目的将解决有关整合素A5功能的三个重要问题：a）整联蛋白A5在CNC开发中的一般作用是什么； b）非CNC细胞中整合素A5的表达如何影响CNC及其衍生物的发展； c）是促进相关咽弓细胞类型中生长因子信号传导所需的整联蛋白A5。为了解决这些问题，我们提出了以下三个具体目的：i）检验以下假设：itga5需要调节CNC祖细胞的生存和增殖； ii）检验以下假设：iTga5在非CNC细胞中的表达是AAAS形成和/或重塑所必需的； iii）确定AAA发育过程中itga5功能的细胞和分子机制。该项目完成后，我们将对整联蛋白A5在AAA发育和正常的AAA形态发生过程中的功能有很大的了解。