Targeting ER Stress To Treat Aortic Aneurysms and Dissections

针对内质网应激治疗主动脉瘤和夹层

基本信息

批准号：
9338945
负责人：
SCOTT A LEMAIRE
金额：
$ 4.52万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-16 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9338945
关键词：
Angiotensin II Aorta Aortic Aneurysm Aortic Diseases Aortic Rupture Biomechanics Cardiovascular Diseases Cause of Death Cell Death Cell Survival Cell physiology Cells Cellular Stress Response Cessation of life Clinical Data Development Dilatation - action Disease Disease Progression Dissection Endoplasmic Reticulum Failure Functional disorder Gene Activation Gene Expression Genes Genetic Transcription IRF3 gene Inflammation Inflammatory Inflammatory Response Infusion procedures Interferons Investigation Life Mediating Metabolic stress Mission Modeling Molecular Morbidity - disease rate Mus National Heart, Lung, and Blood Institute Necrosis Operative Surgical Procedures Pathway interactions Patients Pharmaceutical Preparations Pharmacological Treatment Pharmacology Phenylbutyrates Phosphorylation Population Prevention Process Protein Biosynthesis Public Health RIPK3 gene Research Role Rupture Smooth Muscle Myocytes Sting Injury Stress Testing Therapeutic Agents Thoracic Aortic Aneurysm Tissues Treatment Efficacy United States amlexanox base biological adaptation to stress cell dedifferentiation endoplasmic reticulum stress hemodynamics improved in vivo ineffective therapies innovation insight knock-down mortality myocardin novel novel therapeutic intervention novel therapeutics prevent protein folding protein misfolding public health relevance response sensor therapeutic evaluation therapeutic target transcription factor

项目摘要

DESCRIPTION (provided by applicant): Aortic aneurysms and dissections (AAD) carry significantly high morbidity and mortality. Unfortunately, no clinically proven medication is available to prevent disease progression. There is a critical need to develop effective pharmacological strategies to treat the disease. This project focuses on sporadic AAD which account for more than 80% of cases. One of the significant features of sporadic AAD is progressive smooth muscle cell (SMC) dysfunction and depletion, for which the underlying molecular mechanisms are poorly understood. The aortic wall is constantly exposed to various insults such as hemodynamic disturbance, inflammatory factors and metabolic stress. These factors can interfere with normal cellular functions. Protein biosynthesis and folding in the endoplasmic reticulum (ER) is particularly vulnerable to stress. Disruption in this process causes protein misfolding and ER stress, which in turn can amplify stress and induce a cellular inflammatory response that leads to cell dysfunction, dedifferentiation, and even cell death. The overall objectives of this application are to determine the role of ER stress and ER stress sensor STING in aortic destruction, and the extent to which this mechanism represents a therapeutic target against AAD. We propose 3 specific aims. In Aim 1, we will investigate the mechanisms by which the ER stress-STING pathway induces SMC dysfunction and depletion. Aim 1A, we will test the hypothesis that the ER stress-STING pathway, through IRF3, inhibits myocardin/SRF-mediated transcription of SMC genes, and induces SMC dedifferentiation and dysfunction. Aim 1B, we will test the hypothesis that the ER stress-STING pathway promotes RIP3/ MLKL phosphorylation/activation and induces SMC necroptosis. In Aim 2, we will define the role of the ER stress-STING pathway in biomechanical failure and AAD formation in vivo. Aim 2A, we will test the hypothesis that ER stress pro- motes SMC dedifferentiation and depletion, and thus renders the aortic wall vulnerable to hemodynamic stress and susceptible to AAD formation. Aim 2B, we will test the hypothesis that STING is critically involved in AAD development by inducing SMC dedifferentiation, necroptosis and depletion. In Aim 3, we will test the therapeutic potential of targeting the ER stress-STING pathway for AAD treatment. We will test the hypothesis that pharmacologically reducing ER stress (e.g. with phenylbutyrate) or preventing STING activation (e.g. with amlexanox) will prevent SMC aortic destruction and disease progression. The proposed research is significant because it will not only provide novel molecular insights into AAD development, but also test a new therapeutic approach to prevent disease progression by reducing ER stress and blocking its detrimental response. Our study is also significant because the novel mechanisms on SMC dedifferentiation and necroptosis have broad implications in many other cardiovascular diseases. This research is innovative because it investigates the ER stress-STING pathway in AAD development, which has not been examined before. This study is a novel mechanistic investigation of necroptosis that triggers significant tissue destruction and inflammation.

描述（申请人）：主动脉瘤和纪律处分（AAD）具有明显的病态和死亡率（SMC）功能障碍和耗尽，用于基础的分子机制较差，这些因素可能会造成各种干扰和ER应激，这可以扩大应力并诱导导致细胞功能障碍的细胞炎症反应，甚至细胞的总体目标是确定ER应力应力感传感器在主动脉破坏中的作用，以及该机制的程度压制动脉粥样硬化的目标。我们提出了3个特定目标SMC基因的转录和诱导和功能障碍。 ERSthway在生物力学失败和AAD AIM 2A中的作用，我们将测试以下假设，即应压力smc smc deDiffffrentiation和Depletion，从而使主动脉应激症和血液动力学应力和敏感性有关。通过在AIM 3中诱导SMC脱脂，坏死性和耗竭。 OS的研究很重要，因为它会通过减少ER压力并阻止其有害的反应来进行AAD发展的洞察力。对坏死性的NOCHANISIST研究会触发大量的组织诱发和炎症。