Pro-inflammatory Pyroptotic Cell Death in Aortic Degeneration

主动脉变性中的促炎焦亡细胞死亡

基本信息

批准号：
10643934
负责人：
SCOTT A LEMAIRE
金额：
$ 60.11万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10643934
关键词：
Aorta Aortic Diseases Aortic Injury Apoptosis Atherosclerosis Biomechanics Cardiovascular Diseases Cause of Death Cell Death Cell membrane Cells Clinical Cytosol DNA DNA Damage DNA-dependent protein kinase Data Development Diabetic Angiopathies Dilatation - action Disease Disease Progression Dissection Emergency Situation Event Extracellular Matrix Extravasation Failure Genetic Diseases Goals Heart failure Hypertension In Vitro Inflammation Inflammatory Knockout Mice Learning Life Link Marfan Syndrome Mediating Mission Mitochondria Modeling Molecular Mus National Heart, Lung, and Blood Institute Necrosis Operative Surgical Procedures Oxidative Stress Oxidative Stress Induction Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Phosphorylation Phosphotransferases Prevention Public Health Research Role Rupture Series Signal Pathway Signal Transduction Smooth Muscle Myocytes Stimulator of Interferon Genes Sting Injury Structure TBK1 gene Testing Thoracic Aortic Aneurysm Tissues United States VDAC1 gene Vascular Diseases Work ascending aorta experimental study improved in vivo inhibitor knock-down mouse model novel pharmacologic prevent sensor therapeutic target treatment strategy

项目摘要

Project Summary Ascending thoracic aortic aneurysms and dissections (ATAAD), either associated with genetic conditions or spontaneous as sporadic ATAAD, are extremely lethal diseases that often present as surgical emergencies. Unfortunately, no clinically proven medication is available to prevent sporadic ATAAD progression. There is a critical need to develop effective pharmacological strategies to treat ATAAD. The hallmark of sporadic ATAAD is progressive aortic smooth muscle cell (SMC) depletion and extracellular matrix (ECM) destruction leading to aortic dilatation, dissection, and ultimately rupture. Our long-term goal is to improve our understanding of the molecular pathogenesis of sporadic ATAAD in hope of developing new pharmacological strategies to prevent disease progression. Our preliminary studies suggest that damaged DNA in SMCs activates a pore-forming protein, gasdermin D (GSDMD), that drives SMC pyroptosis, an inflammatory form of programmed cell death that may represent a common pathway to aortic SMC loss. Therefore, the objectives of this application are to determine the role and mechanisms of GSDMD-mediated SMC pyroptosis in ATAAD development and to ex- amine the extent to which cytosolic DNA sensing and pyroptosis represent therapeutic targets against ATAAD. Our central hypothesis is that sensor pathways triggered by damaged DNA activate GSDMD-mediated SMC pyroptosis, leading to aortic degeneration, dissection, and rupture. In Aim 1, we will determine the role of GSDMD-mediated SMC pyroptosis in ATAAD formation. We will test the hypothesis that GSDMD-mediated SMC pyroptosis is critically involved in aortic degeneration, biomechanical failure, and ATAAD development by examining these aspects in Gsdmd-/-mice and inducible SMC-specific Gsdmd knockout mice in our established sporadic ATAAD model. In Aim 2, we will investigate the mechanisms underlying the activation of GSDMD- mediated SMC pyroptosis. In a series of in vitro and in vivo experiments, we will test the hypothesis that cyto- solic DNA-triggered cGAS-STING sensor signaling, through TBK1/IKK2/DNA-PK kinases, directly phosphory- lates GSDMD and promotes its activation and pore formation in plasma membranes, leading to mitochondrial damage and ultimately pyroptotic SMC death. In Aim 3, we will determine the extent to which suppressing cy- tosolic DNA sensing and pyroptotic cell death will prevent ATAAD development and progression. We will test the hypothesis that simultaneously blocking the cGAS-STING pathway and pyroptosis will prevent aortic de- struction and disease progression in our sporadic ATAAD model. We expect that this work will determine how damaged DNA induces pyroptosis and thereby compromises the structure and function of the ascending aortic wall. The positive impact of this work will be an improved understanding of the molecular mechanisms that cause SMC pyroptosis in the development of aortic degeneration, providing an exciting new direction for treat- ment strategies for preventing ATAAD formation and its fatal sequelae. The novel mechanisms regarding DNA damage-induced pyroptotic cell death will also have broad implications in many other cardiovascular diseases. 1

项目摘要上升胸主动脉瘤和解剖（ATAAD），要么与遗传条件或自发作为零星的ATAAD，是非常致命的疾病，通常是手术紧急情况。不幸的是，没有临床证明的药物可以防止零星的ATAAD进展。有一个制定有效的药理策略来治疗ATAAD的迫切需要。零星的标志是进行性主动脉平滑肌细胞（SMC）耗竭和细胞外基质（ECM）破坏，导致主动脉扩张，解剖和最终破裂。我们的长期目标是提高我们对零星ATAAD的分子发病机理，希望制定新的药理策略以防止疾病进展。我们的初步研究表明，SMC中DNA损坏会激活孔形成蛋白质，加油D（GSDMD），驱动SMC凋亡，这是一种程序性细胞死亡的炎症形式这可能代表了主动脉SMC损失的常见途径。因此，此应用程序的目标是确定GSDMD介导的SMC凋亡在ATAAD发育中的作用和机制，并进行胺胞质DNA感应和凋亡代表针对ATAAD的治疗靶标的程度。我们的中心假设是由受损的DNA激活GSDMD介导的SMC触发的传感器途径凋亡，导致主动脉退化，解剖和破裂。在AIM 1中，我们将确定 GSDMD介导的ATAAD形成中的SMC凋亡。我们将测试GSDMD介导的假设 SMC凋亡与主动脉变性，生物力学衰竭和ATAAD发育有关在我们已建立的零星的ATAAD模型。在AIM 2中，我们将研究GSDMD-激活的基础机制介导的SMC凋亡。在一系列体外和体内实验中，我们将检验以下假设。通过TBK1/IKK2/DNA-PK激酶，粒子DNA触发的CGAS刺激传感器信号传导直接磷酸 LATES GSDMD并促进其在质膜中的激活和孔形成，导致线粒体损坏并最终凋亡SMC死亡。在AIM 3中，我们将确定抑制Cy-的程度抗毒DNA感应和凋亡细胞死亡将防止ATAAD发育和进展。我们将测试同时阻止CGAS刺和凋亡的假设将阻止主动脉de骨我们零星的ATAAD模型中的造成和疾病进展。我们希望这项工作将决定如何受损的DNA诱导凋亡，从而损害上升主动脉的结构和功能墙。这项工作的积极影响将是对分子机制的一种改进的理解引起SMC凋亡的发展，在主动脉变性的发展中，为治疗的新方向提供了令人兴奋的新方向预防ATAAD形成及其致命后遗症的策略。关于DNA的新型机制损伤引起的凋亡细胞死亡也将在许多其他心血管疾病中具有广泛的影响。 1