Mitochondrial Damage-Induced Necroptotic Cell Death in SporadicAscending Thoracic Aortic Aneurysms and Dissections

散发性升主动脉瘤和夹层中线粒体损伤诱导的坏死性细胞死亡

基本信息

批准号：
9980977
负责人：
SCOTT A LEMAIRE
金额：
$ 39.63万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-15 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9980977
关键词：
Angiotensin II Aorta Aortic Diseases Apoptotic Area Attention Biomechanics Cardiovascular Diseases Cause of Death Cell Death Cell membrane Cells Cellular Stress Cessation of life Clinical Coupled Cyclic GMP Cytosol DNA Development Dilatation - action Disease Disease Progression Dissection Electron Microscopy Extracellular Matrix Failure Genetic Diseases Goals High Fat Diet Inflammation Inflammatory Infusion procedures Knock-out Knockout Mice Life Lytic Marfan Syndrome Mediating Membrane Mission Mitochondria Mitochondrial DNA Modeling Molecular Mus National Heart, Lung, and Blood Institute Necrosis Nonlytic Operative Surgical Procedures Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Pharmacology Phosphotransferases Prevention Process Protein Kinase Public Health RIPK1 gene RIPK3 gene Reaction Reactive Oxygen Species Research Role Rupture Signal Pathway Signal Transduction Smooth Muscle Myocytes Stimulator of Interferon Genes Swelling TANK-binding kinase 1 TBK1 gene Testing Thoracic Aortic Aneurysm Tissues Trauma United States aged ascending aorta cell injury cell type experimental study improved inhibitor/antagonist insight mouse model novel prevent sensor therapeutic evaluation therapeutic target

项目摘要

Project Summary/Abstract (30 lines) Ascending thoracic aortic aneurysms and dissections (ATAAD) are extremely lethal surgical diseases. ATAAD occurs either in association with genetic conditions or spontaneously as sporadic ATAAD, which accounts for more than 80% of ATAAD. Unfortunately, no clinically proven medication is available to prevent sporadic ATAAD progression. There is a critical need to develop effective pharmacological strategies to treat these diseases. This project focuses on sporadic ATAAD. One of the significant features of sporadic ATAAD is progressive smooth muscle cell (SMC) depletion, for which the underlying mechanisms are poorly understood. Necrotic cell death, a type of cell death characterized by cell swelling and membrane rupture, causes the release of “toxic” molecules from dying cells, leading to further damage of surrounding cells and extracellular matrix and a profound pro-inflammatory reaction. Necrotic cell death is regulated by a programmed process called necroptosis. Mitochondrial damage, often observed in aged or stressed cells, is a potent trigger for necrotic cell death. The overall objective of this application is to determine the role of mitochondrial damage and SMC necroptosis in the development of TAAD; and the extent to which this mechanism represents a therapeutic target against ATAAD. Our central hypotheses are: (1) mitochondrial damage and subsequent release of mtDNA trigger the cytosolic DNA sensor cGAS-STING-TBK1 signaling pathway, which activates the RIP3-MLKL pathway and induces SMC necroptosis, contributing to aortic damage and ATAAD formation; and (2) reducing mitochondrial damage or inhibiting SMC necroptosis will prevent aortic destruction and ATAAD progression. We will test these hypotheses via 3 aims. Aim 1. We will test the hypothesis that mitochondrial damage and subsequent release of mtDNA activates the cytosolic DNA sensor cGAS-STING-TBK1 signaling pathway, which in turn activates the RIP3-MLKL necroptosis pathway, leading to SMC necrotic death. We will perform serial experiments in cultured SMCs to dissect the signaling leading to necrotic cell death (Aim 1B); and evaluate SMC mitochondrial damage and necrotic cell death in patient tissues by electron microscopy analysis (Aim 1B). Aim 2. We will test the hypothesis that cGAS and RIP3-mediated SMC necroptosis are critically involved in aortic SMC injury, aortic destruction, inflammation, biomechanical failure, and ATAAD development by comparing these aspects in WT mice, cGas-/- mice, Rip3-/- mice, and SMC specific Rip3 knockout mice in a sporadic ATAAD model induced by HFD/Ang II challenge. Aim 3. We will test the hypothesis that pharmacologically reducing mitochondrial damage or necroptosis will prevent aortic destruction and disease progression in our sporadic ATAAD mouse model. The proposed research is significant because it will not only provide novel insight of the molecular mechanisms of sporadic ATAAD development, but also test new treatments for preventing sporadic ATAAD formation and its fatal sequelae. The novel mechanisms of mitochondrial damage-induced SMC necroptosis will also have broad implications in many other cardiovascular diseases.

项目摘要/摘要（30 行）胸主动脉瘤和夹层（ATAAD）是极其致命的外科疾病。发生与遗传条件有关或自发地作为散发性 ATAAD，这解释了不幸的是，没有经过临床验证的药物可以预防散发性的 ATAAD。 ATAAD 进展。迫切需要开发有效的药理学策略来治疗这些疾病。散发性 ATAAD 的显着特征之一是进行性平滑肌细胞 (SMC) 耗竭，其潜在机制尚不明确。坏死性细胞死亡是一种以细胞肿胀和细胞膜破裂为特征的细胞死亡，会导致垂死细胞释放“有毒”分子，导致周围细胞和细胞外基质进一步受损，并产生严重的促炎症反应。坏死性细胞死亡是由称为“反应”的程序化过程调节的。坏死性凋亡通常在衰老或应激细胞中观察到，是坏死的潜在触发因素。该应用的目的是确定线粒体损伤和 SMC 的作用。 TAAD 发展中的坏死性凋亡；以及该机制在多大程度上代表了 ATAAD 的治疗靶点：(1) 线粒体损伤和随后的 mtDNA 释放。触发胞质 DNA 传感器 cGAS-STING-TBK1 信号通路，激活 RIP3-MLKL 通路并诱导 SMC 坏死性凋亡，导致主动脉损伤和 ATAAD 形成；(2) 减少线粒体损伤或抑制 SMC 坏死性凋亡将防止主动脉破坏和 ATAAD我们进步。将通过 3 个目标测试这些假设。目标 1. 我们将测试线粒体损伤和随后 mtDNA 的释放激活胞质 DNA 传感器 cGAS-STING-TBK1 信号通路的假设。转激活 RIP3-MLKL 坏死性凋亡途径，导致 SMC 坏死性死亡。我们将在培养的 SMC 中进行系列实验，以剖析导致坏死性细胞死亡的信号传导（目标 1B）并评估 SMC；通过电子显微镜分析患者组织中的线粒体损伤和坏死细胞死亡（目标 1B）。 2. 我们将检验以下假设：cGAS 和 RIP3 介导的 SMC 坏死性凋亡与主动脉粥样硬化密切相关通过比较 SMC 损伤、主动脉破坏、炎症、生物力学故障和 ATAAD 发展这些方面在 WT 小鼠、cGas-/- 小鼠、Rip3-/- 小鼠和 SMC 特异性 Rip3 敲除小鼠中呈散发性。 HFD/Ang II 攻击诱导的 ATAAD 模型。我们将在我们的散发性 ATAAD 小鼠模型中测试通过药理学减少线粒体损伤或坏死性凋亡将预防主动脉破坏和疾病进展的假设。新颖的见解研究散发性 ATAAD 发展的分子机制，同时也测试预防的新疗法散发性 ATAAD 形成及其致命后遗症。线粒体损伤诱导的新机制。 SMC 坏死性凋亡还将对许多其他心血管疾病产生广泛影响。