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

• 批准号: 9081997
• 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
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9081997
• 关键词: Accounting; Angiotensin II; Angiotensins; Aorta; Aortic Aneurysm; Aortic Diseases; Aortic Rupture; Biomechanics; Cardiovascular Diseases; Cause of Death; Cell Death; Cell physiology; Cells; Cellular Stress Response; Cessation of life; Data; Development; Dilatation - action; Disease; Disease Progression; Dissection; Endoplasmic Reticulum; Failure; Figs - dietary; 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; Necrosis; Operative Surgical Procedures; Pathway interactions; Patients; Pharmaceutical Preparations; Phenylbutyrates; Phosphorylation; Population; Prevention; Process; Protein Biosynthesis; Public Health; RIPK3 gene; Research; Role; Rupture; Smooth Muscle Myocytes; Sting Injury; Stress; Testing; Therapeutic; Therapeutic Agents; Thoracic Aortic Aneurysm; Tissues; United States; Work; 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 target; transcription factor

 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（由申请人提供）：主动脉瘤和夹层（AAD）的发病率和死亡率非常高。不幸的是，没有经过临床证明的药物可以预防疾病进展。迫切需要开发有效的药理学策略来治疗该疾病。该项目重点关注占病例 80% 以上的散发性 AAD。散发性 AAD 的显着特征之一是进行性平滑肌细胞 (SMC) 功能障碍和耗竭，但对其潜在的分子机制知之甚少。主动脉壁不断受到血流动力学紊乱、炎症因子和代谢应激等各种损伤。这些因素会干扰正常的细胞功能。内质网 (ER) 中的蛋白质生物合成和折叠特别容易受到压力的影响。这一过程的破坏会导致蛋白质错误折叠和内质网应激，进而放大应激并诱导细胞炎症反应，导致细胞功能障碍、去分化，甚至细胞死亡。本申请的总体目标是确定 ER 应力和 ER 应力传感器 STING 在主动脉破坏中的作用，以及该机制在多大程度上代表 AAD 的治疗靶点。我们提出了 3 个具体目标。在目标 1 中，我们将研究 ER 应激-STING 通路诱导 SMC 功能障碍和耗竭的机制。目标 1A，我们将检验以下假设：ER 应激-STING 通路通过 IRF3 抑制心肌素/SRF 介导的 SMC 基因转录，并​​诱导 SMC 去分化和功能障碍。目标 1B，我们将测试 ER 应激-STING 通路促进 RIP3/MLKL 磷酸化/激活并诱导 SMC 坏死性凋亡的假设。在目标 2 中，我们将定义 ER 应激-STING 通路在体内生物力学失效和 AAD 形成中的作用。目标 2A，我们将检验以下假设：ER 应激促进 SMC 去分化和耗竭，从而使主动脉壁容易受到血流动力学应激的影响，并容易形成 AAD。目标 2B，我们将检验以下假设：STING 通过诱导 SMC 去分化、坏死性凋亡和耗竭，在 AAD 发展中发挥重要作用。在目标 3 中，我们将测试针对 ER 应激-STING 通路治疗 AAD 的治疗潜力。我们将检验以下假设：通过药理学降低 ER 应激（例如使用苯丁酸）或防止 STING 激活（例如使用氨来呫诺）将阻止 SMC 主动脉破坏和疾病进展。拟议的研究意义重大，因为它不仅将为 AAD 的发展提供新的分子见解，而且还将测试一种新的治疗方法，通过减少 ER 应激并阻止其有害反应来预防疾病进展。我们的研究也很重要，因为 SMC 去分化和坏死性凋亡的新机制在许多其他心血管疾病中具有广泛的影响。这项研究具有创新性，因为它研究了 AAD 发展中的 ER 应激-STING 通路，而此前尚未对此进行过研究。这项研究是对引发显着组织破坏和炎症的坏死性凋亡的新机制研究。