Targeting the Sirt-1 pathway to modulate inflammation during murine Kawasaki Disease vasculitis

项目摘要 川崎病(KD)是美国儿童获得性心脏病的主要原因，是一种急性 发热性疾病和系统性血管炎被认为是导致冠状动脉动脉瘤的感染性病原学 并可能导致长期的心血管后遗症。25%的未经治疗的人发展为冠状动脉动脉瘤 KD儿童，导致缺血性心脏病和心肌梗死。而静脉注射免疫球蛋白 静脉注射免疫球蛋白(IVIG)治疗将这一比例降低到5%，高达20%的KD患者对IVIG具有抵抗力，并有更大的风险 冠脉发炎。对免疫和病理机制有更好的了解 KD血管炎的发展需要寻找更有效的KD治疗方法，并防止长期 由组织炎症和冠状动脉重塑引起的心血管后遗症。在初步研究中 使用KD血管炎的小鼠模型，我们发现与炎症反应和IL-1相关的基因 信号在发炎的腹主动脉中上调。此外，组蛋白Sirtuin 1(SIRT1)的表达 以心脏保护功能著称的脱乙酰酶在小鼠炎症的腹主动脉中减少。 在KD血管炎期间。因此，该R01应用程序的中心假设是SIRT1起着关键作用 在通过促进自噬/有丝分裂吞噬来预防细菌配体诱导的IL-1β驱动的血管炎方面， 损害NLRP3炎性小体激活和IL-1β的产生。为了检验这一假设，我们将完成 目的如下：1)确定SIRT1的表达模式及其在细菌配体中的作用 诱导的KD血管炎和2)确定SIRT1活性调节LCWE的机制。 诱导性KD血管炎。这项提议具有很高的翻译潜力，并将决定化合物 已知激活和增加SIRT1活性将改善或减轻KD的心血管病理。重要的是 这些研究不仅将阐明SIRT1如何影响KD急性发作期的炎症反应 阶段，但也将提供对SIRT1调节作为预防 长期的KD心血管并发症。此外，考虑到IL-1信号在体内的既定作用 动脉粥样硬化，我们的发现可能会为广泛的心血管疾病提供新的治疗方向 疾病。

PROJECT ABSTRACT Kawasaki disease (KD), the leading cause of acquired heart disease among children in the US, is an acute febrile illness and systemic vasculitis believed to be of infectious etiology that causes coronary artery aneurysms and can result in long-term cardiovascular sequelae. Coronary artery aneurysms develop in 25% of untreated KD children, leading to ischemic heart disease and myocardial infarction. While intravenous immunoglobulin (IVIG) treatment lowers this rate to 5%, up to 20% of KD patients are IVIG-resistant and have a greater risk for coronary inflammation. A better understanding of the immune and pathological mechanisms leading to the development of KD vasculitis is needed to identify more efficacious KD therapeutics and prevent the long-term cardiovascular sequelae stemming from tissue inflammation and coronary remodeling. In preliminary studies using a murine model of KD vasculitis, we discovered that genes related to inflammatory responses and IL-1 signaling are upregulated in the inflamed abdominal aorta. In addition, expression of Sirtuin 1 (SIRT1), a histone deacetylase known for its cardioprotective functions, was decreased in the inflamed abdominal aorta of mice during KD vasculitis. Therefore, the central hypothesis of this R01 application is that SIRT1 plays a critical role in preventing bacterial ligand-induced IL-1β-driven vasculitis by promoting autophagy/mitophagy, which impairs NLRP3 inflammasome activation and IL-1β production. To test this hypothesis, we will complete the following specific aims: 1) Determine the expression pattern of SIRT1 and its role in bacterial ligand- induced KD vasculitis and 2) Determine the mechanism by which SIRT1 activity modulates LCWE- induced KD vasculitis. This proposal has a very high translational potential and will determine if compounds known to activate and increase SIRT1 activity will improve or reduce cardiovascular pathology of KD. Importantly, these studies will not only shed light on how SIRT1 influences the inflammatory response during the KD acute phase but will also provide insight into the potential of SIRT1 modulation as a therapeutic intervention to prevent long-term KD cardiovascular complications. Moreover, given the established role of IL-1 signaling in atherosclerosis, our findings may illuminate novel therapeutic directions for a broad range of cardiovascular diseases.