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。
基本信息
- 批准号:8469563
- 负责人:
- 金额:$ 36.52万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AddressAffectAortaAortic Arch BranchArteriesBiogenesisBloodBlood CirculationBlood VesselsBranchial arch structureCardiacCardiovascular AbnormalitiesCardiovascular systemCarotid ArteriesCellsChromosomesComplexCongenital AbnormalityCorrosion CastingDataDefectDevelopmentDevelopmental ProcessDiGeorge SyndromeDorsalDown-RegulationEmbryoEndothelial CellsEndotheliumEtiologyFibronectinsFutureGeneticGoalsGrowth FactorHealthHeartHistologyHumanImmunofluorescence MicroscopyImmunohistochemistryIndia ink stainInjection of therapeutic agentIntegrinsLaboratoriesLeadLeftLive BirthLungMaintenanceMediatingMolecularMolecular GeneticsMorphogenesisMusMutagenesisMutant Strains MiceNeural CrestNeural Crest CellNeural tubePathologic ProcessesPathway interactionsPatternPattern FormationPenetrancePermeabilityPhosphorylationPlayPregnancyProcessPulmonary artery structureRoleSideSignal TransductionSmooth Muscle MyocytesStagingStructureStructure of right subclavian arterySyndromeSystemSystems DevelopmentTestingTissuesTreesVenousaortic archcell typecongenital heart disorderfluid flowinfant morbidity/mortalityinsightmalformationmicrodeletionpreventprogenitorresearch studystem cell nichetherapy design
项目摘要
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、肺动脉和主动脉弓动脉(AAA)系统组成-该系统的适当发育对于静脉血和含氧血的分离是必不可少的,并且是人类生存和健康所需的。主动脉弓动脉的异常模式引起严重的出生缺陷,并且通常作为其他先天性综合征的一部分发生,例如DiGeorge综合征,这是人类最常见的染色体微缺失综合征之一(每4000例活产中有1例)。我们的长期目标是了解介导正常AAA发展的分子和遗传途径,以便深入了解AAA病理形态发生期间出错的过程。在我的实验室的实验导致的发现,整合素a5的表达在Isl 1阳性细胞和他们的后代是所需的主动脉弓的发展。我们还发现,整合素a5的存在所需的正常数量的心脏神经嵴(CNC)细胞在咽弓。由于CNC细胞产生AAA的血管平滑肌细胞(VSMCs),并且由于正常形成,招募和与主动脉弓动脉内皮细胞的关联是AAA的适当图案化所需的,因此我们建议找出整合素α 5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整合素α 5的功能的三个重要问题:a)整合素α 5在CNC发展中的一般作用是什么; B)整合素α 5在非CNC细胞中的表达如何影响CNC及其衍生物的发展; c)整合素α 5是促进相关咽弓细胞类型中的生长因子信号传导所必需的。为了解决这些问题,我们提出了以下三个具体目标:I)检验Itga 5是调节CNC祖细胞的存活和增殖所必需的假设; II)检验Itga 5在非CNC细胞中的表达是AAA的形成和/或重塑所必需的假设; III)确定Itga 5在AAA发展期间功能的细胞和分子机制。本研究完成后,我们将对整合素a5在AAA形成中的作用和AAA形态发生的正常过程有重要的认识。
项目成果
期刊论文数量(0)
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会议论文数量(0)
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{{ truncateString('Sophie Astrof', 18)}}的其他基金
Identification of compensatory mechanisms to rescue aortic arch artery defects
确定挽救主动脉弓动脉缺损的代偿机制
- 批准号:
10389147 - 财政年份:2022
- 资助金额:
$ 36.52万 - 项目类别:
Identification of compensatory mechanisms to rescue aortic arch artery defects
确定挽救主动脉弓动脉缺损的代偿机制
- 批准号:
10545745 - 财政年份:2022
- 资助金额:
$ 36.52万 - 项目类别:
Mechanisms regulating the formation of the pharyngeal arch arteries
调节咽弓动脉形成的机制
- 批准号:
9702895 - 财政年份:2017
- 资助金额:
$ 36.52万 - 项目类别:
Mechanisms regulating the formation of the pharyngeal arch arteries
调节咽弓动脉形成的机制
- 批准号:
9540070 - 财政年份:2017
- 资助金额:
$ 36.52万 - 项目类别:
Cell-ECM interactions in the development of the aortic arch arteries
主动脉弓发育中的细胞-ECM 相互作用
- 批准号:
9484520 - 财政年份:2017
- 资助金额:
$ 36.52万 - 项目类别:
Cell-ECM interactions in the development of the aortic arch arteries
主动脉弓发育中的细胞-ECM 相互作用
- 批准号:
9260038 - 财政年份:2010
- 资助金额:
$ 36.52万 - 项目类别:
Role of integrin a5b1 in vascular patterning and the formation of the pharyngeal arch arteries
整合素 a5b1 在血管模式和咽弓动脉形成中的作用
- 批准号:
10316381 - 财政年份:2010
- 资助金额:
$ 36.52万 - 项目类别:
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:
8669807 - 财政年份:2010
- 资助金额:
$ 36.52万 - 项目类别:
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:
8089389 - 财政年份:2010
- 资助金额:
$ 36.52万 - 项目类别:
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 - 财政年份:2010
- 资助金额:
$ 36.52万 - 项目类别:
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