Macrophage Pyroptosis in Abdominal Aortic Aneurysm

腹主动脉瘤巨噬细胞焦亡

• 批准号: 10532383
• 负责人: Congqing Wu
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10532383
• 关键词: Abdominal Aortic Aneurysm; Address; Angiotensin II; Aorta; Aortic Aneurysm; Aortic Diseases; Aortic Rupture; Apoptosis; Biology; CASP1 gene; Caspase; Cell membrane; Cell surface; Cells; Cessation of life; Coagulation Process; Data; Death Rate; Disseminated Intravascular Coagulation; Event; Genetic; Human; Inflammation; Inflammatory; Lesion; Macrophage; Mediating; Medical; Medicine; Mus; Nature; Pathologic; Phosphatidylserines; Proteins; Publications; Research; Research Personnel; Role; Rupture; Ruptured Abdominal Aortic Aneurysm; Surface; Testing; Thromboplastin; Thrombus; Tissues; Training; biobank; career development; college; innovation; monolayer; novel; prevent; release factor; research and development; septic; therapeutic target

The purpose of this K99/R00 application is to (1) provide me with necessary training in research and career development for my transition to a successful independent researcher; (2) study the role of pyroptosis, a novel form of programmed cell death, in the rupture of Abdominal Aortic Aneurysm (AAA). AAA is a progressive pathological dilation and weakening of the aorta. AAA is associated with extreme rates of death (up to 80%) in the event of aortic rupture. There has no medical therapy to prevent or treat aortic rupture, which is largely attributed to that mechanisms underlying AAA rupture have not been defined. AAA is characterized by inflammation and frequent presence of thrombus. Inflammatory lesions often contain dead cells. Until recently, programmed cell death was thought to occur only in one form, called “apoptosis”. In 2015 and 2016, four Nature publications from three groups revealed gasdermin D (GSDMD)-dependent mechanisms of pyroptosis. GSDMD forms pores on cell surface and ruptures cell membrane. In ruptured cell membrane, phosphatidylserine, which is exclusively located in the inner monolayer in living cells, freely flip into outer monolayer and forms a procoagulant surface for tissue factor by facilitating the assembly of proteins of clotting cascade. We recently discovered that macrophage pyroptosis caused septic death through tissue factor release, which triggered disseminated intravascular coagulation in mice. My preliminary data show that genetic deficiency of GSDMD protects against AAA rupture in angiotensin II-infused mice. In this proposal, I will test the hypothesis that macrophage pyroptosis promotes AAA rupture through tissue factor-dependent thrombus propagation. Two aims will be addressed to test this hypothesis. In Aim 1, I will profile macrophage pyroptosis in angiotensin II-induced AAA rupture using caspase-1 and Caspase-11 deficient mice (K99 PHASE). In Aim 2, I will determine how macrophage pyroptosis, through tissue factor-mediated mechanisms, contributes to AAA rupture (R00 PHASE). Together I will examine the causal relationship between thrombus and AAA rupture and test the concept of a feedforward loop between macrophage pyroptosis and tissue factor/thrombus until AAA rupture. This project is important because GSDMD and pyroptosis may represent a therapeutic target. This project is innovative because it defines a novel procoagulant mechanism in AAA. I will also examine macrophage biology and pyroptosis in human aortic aneurysm tissues available in Dr. LeMaire’s Aortic Disease Biobank at Baylor College of Medicine to enhance the translational aspects of my proposed research.

该K99/R00应用程序的目的是（1）为我提供了研究的必要培训和 我向成功的独立研究人员过渡的职业发展； （2）研究 凋亡是一种编程细胞死亡的一种新型形式，在腹主动脉瘤（AAA）破裂中。 AAA是渐进的病理词典，主动脉的弱化。 AAA与极端有关 如果主动脉破裂，死亡率（高达80％）。没有医疗治疗可以预防或治疗 主动脉破裂，这主要归因于AAA破裂的基础机制 定义。 AAA的特征是炎症和经常存在血栓。炎症病变 通常包含死细胞。直到最近，被编程的细胞死亡才被认为仅以一种形式发生， 称为“凋亡”。在2015年和2016年，来自三个小组的四个自然出版物揭示了Gasdermin D （GSDMD） - 依赖性凋亡的机制。 GSDMD在细胞表面形成毛孔并破裂细胞 膜。在破裂的细胞膜中，磷脂酰丝氨酸，仅位于内部 活细胞中的单层，自由翻转进入外部单层，并形成组织的表面 通过支持服装级联蛋白质的组装来进行因素。我们最近发现 巨噬细胞凋亡通过组织因子释放引起败血性死亡，这引发了传播 小鼠血管内凝血。我的初步数据表明，GSDMD的遗传缺乏保护 针对血管紧张素II注入的小鼠的AAA破裂。在此提案中，我将检验以下假设 巨噬细胞凋亡通过组织因子依赖性血栓传播促进AAA破裂。 将解决两个目标以检验这一假设。在AIM 1中，我将在 血管紧张素II使用caspase-1和caspase-11缺乏小鼠（K99期）诱导AAA破裂。在 aim 2，我将通过组织因子介导的机制来确定巨噬细胞的凋亡如何 有助于AAA破裂（R00期）。我将一起研究 血栓和AAA破裂，并测试巨噬细胞吞噬之间的前馈环的概念 和组织因子/血栓直至AAA破裂。该项目很重要，因为GSDMD和凋亡 可能代表治疗靶标。该项目具有创新性，因为它定义了一种新颖的探针 AAA中的机制。我还将检查人主动脉瘤中的巨噬细胞生物学和凋亡 Lemaire博士在贝勒医学院的主动脉疾病生物库中提供的组织可增强 我提出的研究的翻译方面。