Targeting ER Stress To Treat Aortic Aneurysms and Dissections

 描述(由申请人提供)：主动脉瘤和夹层(AAD)具有相当高的发病率和死亡率。不幸的是，没有经过临床验证的药物可以防止疾病的发展。迫切需要开发有效的药理学策略来治疗这种疾病。本项目以散发性AAD为主，占病例的80%以上。散发性AAD的一个重要特征是进行性平滑肌细胞(SMC)功能障碍和耗竭，其潜在的分子机制尚不清楚。主动脉壁不断地暴露在各种损伤中，如血流动力学障碍、炎症因子和代谢应激。这些因素会干扰正常的细胞功能。内质网(ER)中蛋白质的生物合成和折叠特别容易受到压力的影响。这一过程的中断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。这项应用的总体目标是确定ER应激和ER应激感应器刺在主动脉破坏中的作用，以及这一机制在多大程度上代表了AAD的治疗靶点。我们提出了三个具体目标。在目标1中，我们将研究内质网应激途径导致SMC功能障碍和耗竭的机制。目的1、我们将验证内质网应激途径通过IRF3抑制Myocardin/SRF介导的SMC基因转录，并诱导SMC去分化和功能障碍的假说。目的1B，我们将验证内质网应激通路促进RIP3/MLKL磷酸化/激活并诱导SMC坏死性下垂的假说。在目标2中，我们将确定内质网应激-刺痛通路在体内生物力学失败和AAD形成中的作用。目的：我们将验证内质网应激促进SMC去分化和耗竭，从而使主动脉壁易受血流动力学应力和AAD形成的假说。目的2B，我们将通过诱导SMC去分化、坏死性下垂和耗竭来验证STING在AAD发生中起关键作用的假说。在目标3中，我们将测试靶向内质网应激刺激通路治疗AAD的治疗潜力。我们将测试这一假设，即从药物上减少ER应激(例如，使用苯丁酸酯)或防止刺痛激活(例如，使用氨来昔诺)将防止SMC主动脉破坏和疾病进展。这项拟议的研究具有重要意义，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，通过减少内质网应激并阻断其有害反应来防止疾病进展。我们的研究也很有意义，因为SMC脱分化和坏死性下垂的新机制在许多其他心血管疾病中都有广泛的意义。这项研究具有创新性，因为它研究了AAD发育过程中的内质网应激刺激途径，这是以前从未被研究过的。这项研究是对引发严重组织破坏和炎症的坏死性下垂的一项新的机制研究。

 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.