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：
10239058
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 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10239058
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）上升的胸动脉瘤和解剖（ATAAD）是极具致命的手术疾病。 ataad 发生与遗传条件相关，或者自发作为零星的ataad，这是超过80％的ATAAD。不幸的是，没有临床证明的药物可以防止零星 ataad的进展。迫切需要制定有效的药物策略来治疗这些疾病。该项目侧重于零星的ATAAD。零星ATAAD的重要特征之一是渐进的平滑肌细胞（SMC）部署，对此，基本机制对此知之甚少。坏死细胞死亡是一种以细胞吞咽和膜破裂为特征的细胞死亡，导致垂死细胞中“有毒”分子的释放，从而导致周围细胞和细胞外基质进一步损害，并产生深刻的促炎反应。坏死细胞死亡受称为的程序过程调节坏死性。线粒体损伤通常在老年或应力的细胞中观察到，是坏死的潜在触发因素细胞死亡。该应用的总体目的是确定线粒体损伤和SMC的作用 TAAD发展中的坏死性；以及这种机制代表对ATAAD的治疗靶标的程度。我们的中心假设是：（1）线粒体损伤和随后释放mtDNA 触发胞质DNA传感器CGAS-sting-TBK1信号通路，该途径激活RIP3-MLKL途径并诱导SMC坏死性，导致主动脉损伤和ATAAD形成；（2）减少线粒体损伤或抑制SMC坏死性会防止主动脉损伤和ATAAD进展。我们将通过3个目标检验这些假设。 AIM 1。我们将检验以下假设：线粒体损伤和随后的mtDNA释放激活胞质DNA传感器CGAS cGAS-sting-TBK1信号通路，该途径在转弯激活RIP3-MLKL坏死途径，导致SMC坏死死亡。我们将在培养的SMC中进行串行实验，以剖析导致坏死细胞死亡的信号传导（AIM 1B）；并评估SMC 通过电子显微镜分析（AIM 1B），患者组织中的线粒体损伤和坏死细胞死亡。目的 2。我们将检验以下假设：CGA和RIP3介导的SMC坏死症主要参与主动脉通过比较 WT小鼠，CGA-/ - 小鼠，RIP3 - / - 小鼠和SMC特异性RIP3敲除小鼠的这些方面由HFD/ANG II挑战引起的ATAAD模型。 AIM 3。我们将检验以下假设：在我们零星的ATAAD小鼠模型中，药理学上减少线粒体损伤或坏死性会预防主动脉损害和疾病进展。拟议的研究很重要，因为它不仅会提供新颖的见解零星ataad发育的分子机制，但也测试了新的治疗方法零星的ataad形成及其致命后遗症。线粒体损伤引起的新型机制 SMC坏死性也将在许多其他心血管疾病中具有广泛的影响。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Early Detection of Aortic Degeneration in a Mouse Model of Sporadic Aortic Aneurysm and Dissection Using Nanoparticle Contrast-Enhanced Computed Tomography.

DOI：
10.1161/atvbaha.120.315210
发表时间：
2021-04
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
0
作者：
Ghaghada KB;Ren P;Devkota L;Starosolski Z;Zhang C;Vela D;Stupin IV;Tanifum EA;Annapragada AV;Shen YH;LeMaire SA
通讯作者：
LeMaire SA

New Technologies With Increased Precision Improve Understanding of Endothelial Cell Heterogeneity in Cardiovascular Health and Disease.

DOI：
10.3389/fcell.2021.679995
发表时间：
2021
期刊：
Frontiers in cell and developmental biology
影响因子：
5.5
作者：
Dawson A;Wang Y;Li Y;LeMaire SA;Shen YH
通讯作者：
Shen YH

Exome-wide evaluation of rare coding variants using electronic health records identifies new gene-phenotype associations.

DOI：
10.1038/s41591-020-1133-8
发表时间：
2021-01
期刊：
Nature medicine
影响因子：
82.9
作者：
Park J;Lucas AM;Zhang X;Chaudhary K;Cho JH;Nadkarni G;Dobbyn A;Chittoor G;Josyula NS;Katz N;Breeyear JH;Ahmadmehrabi S;Drivas TG;Chavali VRM;Fasolino M;Sawada H;Daugherty A;Li Y;Zhang C;Bradford Y;Weaver J;Verma A;Judy RL;Kember RL;Overton JD;Reid JG;Ferreira MAR;Li AH;Baras A;LeMaire SA;Shen YH;Naji A;Kaestner KH;Vahedi G;Edwards TL;Chen J;Damrauer SM;Justice AE;Do R;Ritchie MD;Rader DJ
通讯作者：
Rader DJ

AKT2 regulates endothelial-mediated coagulation homeostasis and promotes intrathrombotic recanalization and thrombus resolution in a mouse model of venous thrombosis.

在静脉血栓形成小鼠模型中，AKT2 调节内皮介导的凝血稳态并促进血栓内再通和血栓溶解。