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.

此K99/R 00申请的目的是（1）为我提供必要的研究培训， 职业发展为我过渡到一个成功的独立研究员;（2）研究的作用 在腹主动脉瘤（AAA）破裂中，细胞凋亡是一种新的程序性细胞死亡形式。 AAA是主动脉的进行性病理性扩张和弱化。AAA与极端 主动脉破裂时的死亡率（高达80%）。没有任何药物可以预防或治疗 主动脉破裂，这在很大程度上归因于AAA破裂的机制， 定义了AAA的特征是炎症和频繁出现血栓。炎性病变 通常含有死细胞。直到最近，程序性细胞死亡被认为只以一种形式发生， 称为“凋亡”。在2015年和2016年，来自三个小组的四篇自然出版物揭示了gasdermin D （GSDMD）依赖性焦亡机制。GSDMD在细胞表面形成孔并使细胞破裂 膜的在破裂的细胞膜，磷脂酰丝氨酸，这是专门位于内 活细胞中的单层，自由翻转成外层单层并形成组织的促凝血表面 凝血因子通过促进凝血级联反应的蛋白质的组装。我们最近发现 巨噬细胞通过组织因子释放引起脓毒性死亡， 小鼠血管内凝血。我的初步数据显示，GSDMD的遗传缺陷 血管紧张素II输注小鼠的AAA破裂。在这份提案中，我将检验一个假设， 巨噬细胞凋亡通过组织因子依赖性血栓传播促进AAA破裂。 两个目标将被解决，以测试这一假设。在目标1中，我将描述 血管紧张素II诱导的AAA破裂使用半胱天冬酶-1和半胱天冬酶-11缺陷小鼠（K99 PHASE）。在 目的2，我将确定如何巨噬细胞焦亡，通过组织因子介导的机制， 导致AAA破裂（R 00阶段）。我将一起研究 血栓和AAA破裂，并测试巨噬细胞焦亡之间前馈回路的概念 和组织因子/血栓直至AAA破裂。这个项目很重要，因为GSDMD和焦亡 可能是治疗靶点。这个项目是创新的，因为它定义了一种新的促凝血剂 AAA机制。我还将研究巨噬细胞生物学和在人类主动脉瘤焦亡 贝勒医学院LeMaire博士的主动脉疾病生物库中的组织， 翻译方面的建议。