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

先天性心脏病是发达国家婴儿死亡和发病的主要原因。心脏的流出血管系统由主动脉、肺动脉和主动脉弓动脉系统（AAAs）组成，该系统的正常发育对静脉血和含氧血的分离至关重要，也是人类生存和健康所必需的。主动脉弓的异常模式会导致严重的出生缺陷，并经常作为其他先天性综合征的一部分发生，如迪乔治综合征，这是人类最常见的染色体微缺失综合征之一（每4000个活产婴儿中就有1个）。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，以便深入了解在AAA的病理形态发生过程中出错的过程。我实验室的实验发现，在isl1阳性细胞及其后代中，整合素a5的表达是主动脉弓发育所必需的。我们还发现整合素a5对于咽弓中正常数量的心脏神经嵴（CNC）细胞的存在是必需的。由于CNC细胞产生了AAAs的血管平滑肌细胞（VSMCs），并且由于AAAs的正常形成，VSMCs与主动脉弓内皮细胞的募集和关联是AAAs正常模式所必需的，因此我们建议找出整合素a5在CNC细胞及其后代VSMCs发育中的作用。我们的具体目标将解决关于integrina5功能的三个重要问题：a) integrina5在CNC发展中的一般作用是什么；b)整合素a5在非CNC细胞中的表达如何影响CNC及其衍生物的发展；C)是整合素a5在相关咽弓细胞类型中促进生长因子信号传导所必需的。为了解决这些问题，我们提出以下三个具体目标：1)验证Itga5是调节CNC祖细胞存活和增殖所必需的假设；II)验证非cnc细胞中Itga5的表达是AAAs形成和/或重塑所必需的假设；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，我们将对整合素a5在AAA发育中的作用和AAA形态发生的正常过程有更深入的了解。

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.