Mechanisms of thoracic aortic aneurysms

胸主动脉瘤的发病机制

• 批准号: 8445201
• 负责人: Alan Daugherty
• 金额: $ 51.11万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8445201
• 关键词: Abdomen; Abdominal Aortic Aneurysm; Address; Affect; Angiotensin II; Anterior; Aorta; Area; Attenuated; Blood; CC chemokine receptor 2; CCL2 gene; Cardiac; Cells; Cessation of life; Complex; Defect; Development; Diagnosis; Disease; Embryo; Endothelial Cells; Fibroblasts; Growth; Health; Heart; Human; Individual; Infiltration; Infusion procedures; Leukocytes; Life; Ligands; Literature; Medial; Mediating; Mediator of activation protein; Medical; Monocyte Chemoattractant Protein-1; Mus; Neural Crest; Operative Surgical Procedures; Pathology; Patients; Pericytes; Population; Public Health; Research; Role; Rupture; Smooth Muscle Myocytes; Source; Specificity; Structure; Surface; Testing; Therapeutic; Thoracic Aortic Aneurysm; Thoracic aorta; Tissues; Tunica Adventitia; Ulcer; ascending aorta; attenuation; base; cell type; chemokine; disease characteristic; insight; macrophage; neutralizing antibody; paracrine; receptor

DESCRIPTION (provided by applicant): Thoracic aortic aneurysms (TAAs) most commonly develop in the ascending region in an asymptomatic manner. Frequently, the first indication of its presence is rupture that commonly leads to death. TAAs are the life-threatening consequence in patients afflicted with a broad range of genetically determined diseases; one of the most common being Marfan's disease. The only current therapeutic strategy for individuals diagnosed with TAAs is surgical options. Consequently, there is a pressing need for mechanistic insight into TAAs to develop effective therapeutics. We have recently demonstrated that AngII infusion also leads to TAAs that are localized to the ascending aorta. AngII-induced TAAs are attenuated by CC Chemokine receptor 2 (CCR2) deficiency. This infers a role for monocyte chemoattractant protein-1 (MCP-1) in TAAs, although CCR2 also interacts with other chemokines. We have recently demonstrated that endothelial-specific deficiency of AT1a receptors imparts a similar degree of attenuation of AngII-induced TAAs as whole body CCR2 deficiency. These two observations could potentially be associated via a paracrine mechanism by which AngII stimulates MCP-1 release, the ligand that determines the major effects of CCR2 stimulation. The AngII-induced TAAs are characterized by profound medial macrophage accumulation that is predominantly on the adventitial aspect. On the basis of this briefly described background, we are proposing to test the central hypothesis that the MCP-1-CCR2 axis promotes AngII-induced TAAs localized to the ascending region through an endothelial-mediated mechanism of macrophage recruitment from the adventitia via aortic region- specific effects. To test this hypothesis, the following specific aims will be addressed: Aim 1. Determine the role of the MCP-1-CCR2 axis in development of AngII-induced TAAs. A. Does whole body deficiency of either MCP-1 or CCR2 promote equivalent reductions in AngII-induced TAAs that are persistent and associated with reduced medial macrophage accumulation? B. Is the source of MCP-1 in promoting TAAs due to AngII releasing this chemokine directly from endothelial or indirectly via specific SMC populations? Aim 2. Determine the origin of medial macrophages accumulating in ascending aortas during development of AngII-induced TAAs. A. What is the sequence of leukocytic infiltration in the development of AngII-induced TAAs and does this correlate to the expression of MCP-1 and CCR2? B. Are macrophages that accumulate in media and adventitia of ascending aortas during AngII infusion derived from blood or tissue origin? C. Is leukocyte accumulation in human ascending aortic aneurysmal tissue associated with MCP-1 and CCR2 expression?

描述（由申请人提供）：胸腔主动脉瘤（TAA）最常见于升序区域以无症状的方式发展。通常，其存在的第一个迹象是通常导致死亡的破裂。 TAA是患有广泛遗传确定疾病的患者的威胁生命的后果。最常见的是马凡氏病。目前针对患有TAA的人的唯一治疗策略是手术选择。因此，迫切需要对TAA的机械洞察力，以开发有效的治疗疗法。 我们最近证明，Angii输注还导致TAA局部局部主动脉。 CC趋化因子受体2（CCR2）缺陷使Angii诱导的TAA衰减。尽管CCR2也与其他趋化因子相互作用，但这还引起了TAA中单核细胞趋化蛋白1（MCP-1）的作用。我们最近证明，AT1A受体的内皮特异性缺陷赋予Angii诱导的TAA与全身CCR2缺乏症相似的衰减程度。这两个观察结果可能通过旁分泌机制与Angii刺激MCP-1释放的旁分泌机制相关联，这是确定CCR2刺激的主要作用的配体。 Angii引起的TAA的特征是内侧巨噬细胞积累的深刻，主要是在外在方面。在此简短描述的背景下，我们提议测试中心假设，即MCP-1-CCR2轴通过主动脉区域特异性效应通过巨噬细胞募集的内皮介导的巨噬细胞募集机制促进了安置到上升区域的Angii诱导的TAA。为了检验这一假设，将解决以下特定目标：目标1。确定MCP-1-CCR2轴在Angii诱导的TAA开发中的作用。答：MCP-1或CCR2的全身缺乏是否会促进持续存在并与内侧巨噬细胞积累减少有关的Angii诱导的TAA的同等减少？ B. MCP-1的来源是由于Angii直接通过特定的SMC种群直接从内皮或间接从内皮释放该趋化因子而引起的TAA的来源？ AIM 2。确定在Angii诱导的TAA发育过程中积累的内侧巨噬细胞的起源。答：在Angii诱导的TAA的发展中，白细胞浸润的序列是什么，这与MCP-1和CCR2的表达相关？ B.在血管或组织起源衍生的Angii输注期间，在培养基和上升主动脉的兴起中积累的巨噬细胞是否积累？ C.与MCP-1和CCR2表达相关的人升主动脉瘤组织中的白细胞积累？