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和发病的主要原因。心脏的流出脉管系统由主动脉、肺动脉和主动脉弓系统 (AAA) 组成 - 该系统的正确发育对于静脉和含氧血液的分离至关重要，也是人类生存和健康所必需的。主动脉弓异常模式会导致严重的出生缺陷，并且经常作为其他先天性综合征的一部分发生，例如迪乔治综合征，这是人类最常见的染色体微缺失综合征之一（每 4000 个活产儿中就有一个）。我们的长期目标是了解介导 AAA 正常发育的分子和遗传途径，以便深入了解 AAA 病理形态发生过程中出错的过程。我实验室的实验发现，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，咽弓中存在正常数量的心脏神经嵴 (CNC) 细胞需要整合素 a5。由于 CNC 细胞产生 AAA 的血管平滑肌细胞 (VSMC)，并且由于 AAA 的正确形成需要 VSMC 的正常形成、募集和与主动脉弓内皮细胞的结合，因此我们建议找出整合素 a5 在 CNC 细胞及其后代 VSMC 的发育中发挥着重要作用。我们的具体目标将解决有关整合素 a5 功能的三个重要问题：a) 整合素 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及其衍生物的发育； c) 整合素 a5 是促进相关咽弓细胞类型中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： I) 检验 Itga5 是调节 CNC 祖细胞存活和增殖所必需的假设； II) 检验非 CNC 细胞中 Itga5 的表达是 AAA 的形成和/或重塑所必需的假设； III)确定Itga5在AAA发育过程中功能的细胞和分子机制。该项目完成后，我们将深入了解整合素 a5 在 AAA 发育中的功能以及 AAA 形态发生的正常过程。