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/R00 申请的目的是 (1) 为我提供必要的研究和培训培训 我向成功的独立研究员过渡的职业发展；（2）研究 细胞焦亡是腹主动脉瘤（AAA）破裂中一种新型的程序性细胞死亡。 AAA 是主动脉的进行性病理性扩张和减弱，与严重程度相关。 主动脉破裂的死亡率（高达 80%） 没有药物可以预防或治疗。 主动脉破裂，这很大程度上归因于 AAA 破裂的机制尚未被阐明 AAA 的特点是炎症和频繁出现的炎症病变。 直到最近，程序性细胞死亡还被认为只以一种形式发生， 2015年和2016年，来自三个研究小组的四篇《自​​然》杂志发表了gasdermin D。 GSDMD 依赖的细胞焦亡机制在细胞表面形成孔并使细胞破裂。 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，自由翻转到外单层并形成组织的促凝血表面 我们最近发现，通过促进凝血级联蛋白质的组装来发挥作用。 巨噬细胞焦亡通过组织因子释放引起脓毒症死亡，从而引发播散性 我的初步数据表明，GSDMD 的遗传缺陷可以保护小鼠的血管内凝血。 抗血管紧张素 II 注射小鼠的 AAA 破裂 在本提案中，我将检验以下假设： 巨噬细胞焦亡通过组织因子依赖性血栓传播促进 AAA 破裂。 将通过两个目标来检验这一假设。在目标 1 中，我将描述巨噬细胞焦亡。 使用 caspase-1 和 Caspase-11 缺陷小鼠（K99 PHASE）进行血管紧张素 II 诱导的 AAA 破裂。 目标 2，我将确定巨噬细胞焦亡如何通过组织因子介导的机制， 我将一起研究 AAA 破裂（R00 阶段）之间的因果关系。 血栓和 AAA 破裂并测试巨噬细胞焦亡之间前馈循环的概念 和组织因子/血栓直至 AAA 破裂 该项目很重要，因为 GSDMD 和细胞焦亡。 该项目具有创新性，因为它定义了一种新型促凝血剂。 我还将研究人类主动脉瘤中的巨噬细胞生物学和细胞焦亡。 贝勒医学院 LeMaire 博士的主动脉疾病生物库中提供的组织可增强 我提出的研究的转化方面。