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）的发病率和死亡率显著较高。不幸的是，没有临床证明的药物可用于预防疾病进展。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的重要特征之一是进行性平滑肌细胞（SMC）功能障碍和消耗，但对其潜在的分子机制知之甚少。主动脉壁经常暴露于各种损伤，如血流动力学紊乱、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）中的蛋白质生物合成和折叠特别容易受到应激的影响。这一过程的中断会导致蛋白质错误折叠和ER应激，这反过来又会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针对AAD的治疗靶标。我们提出三个具体目标。在目的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。目的1A，我们将验证ER应激-STING通路通过IRF 3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设。目的1B，我们将检验ER应激-STING途径促进RIP 3/ MLKL磷酸化/活化并诱导SMC坏死性凋亡的假设。在目标2中，我们将定义ER应力-STING通路在体内生物力学失效和AAD形成中的作用。目的2A，我们将验证ER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激和易受AAD形成的假设。目的2B，我们将检验STING通过诱导SMC去分化、坏死性凋亡和耗竭而关键参与AAD发展的假设。在目标3中，我们将测试靶向ER应激-STING通路用于AAD治疗的治疗潜力。我们将检验以下假设：降低ER应激（例如苯丁酸酯）或防止STING激活（例如氨来昔诺）将防止SMC主动脉破坏和疾病进展。这项研究意义重大，因为它不仅为AAD的发展提供了新的分子见解，而且还测试了一种新的治疗方法，通过减少ER应激和阻断其有害反应来预防疾病进展。我们的研究也很重要，因为SMC去分化和坏死凋亡的新机制在许多其他心血管疾病中具有广泛的意义。这项研究是创新的，因为它研究了AAD发展中的ER应激-STING途径，这在以前没有被研究过。这项研究是一种新的机制调查坏死性凋亡，触发显着的组织破坏和炎症。

 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.