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

靶向 Sirt-1 通路调节小鼠川崎病血管炎期间的炎症

• 批准号: 10281090
• 负责人: Magali Noval Rivas
• 金额: $ 41.75万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10281090
• 关键词: Abdominal Aortic Aneurysm; Acute; Adult; Aneurysm; Antigen-Antibody Complex; Atherosclerosis; Autophagocytosis; Bacteria; Blood Vessels; Cardiovascular Diseases; Cardiovascular Pathology; Cardiovascular system; Case Study; Cell Wall; Cells; Child; Childhood; Chronic; Clinical Trials; Coronary; Coronary Aneurysm; Coronary artery; Data; Deacetylase; Development; Disease; Etiology; Fever; Gene Expression; Genetic; HDAC4 gene; Heart; Heart Diseases; Histologic; Human; Immune; Immune response; Immunoglobulin G; Immunologics; Impairment; In Vitro; Incidence; Infectious Agent; Inflammasome; Inflammation; Inflammation Mediators; Inflammatory Response; Innate Immune Response; Interleukin-1; Interleukin-1 beta; Intravenous Immunoglobulins; Lactobacillus casei; Lead; Lesion; Ligands; Light; Mediating; Modeling; Molecular; Molecular Mimicry; Monoclonal Antibodies; Mucocutaneous Lymph Node Syndrome; Mus; Myocardial Infarction; Myocardial Ischemia; Myocarditis; Pathogenesis; Pathologic; Pathway interactions; Patients; Pattern; Pharmacology; Phase; Play; Prediction of Response to Therapy; Prevention; Process; Production; Recycling; Resistance; Risk; Role; SIRT1 gene; Signal Transduction; Superantigens; Testing; Therapeutic; Therapeutic Intervention; Tissues; Tumor-infiltrating immune cells; Vascular remodeling; Vasculitis; Whole Blood; abdominal aorta; anakinra; cardioprotection; coronary arteritis; coronary fibrosis; experimental study; gene discovery; high risk; improved; infection risk; insight; mitochondrial autophagy; mouse model; novel; novel therapeutics; overexpression; prevent; protective effect; response; stem; therapeutically effective; transcriptome; vascular inflammation; vascular injury

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.

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瘤的感染性病因 并可能导致长期的心血管后遗症。 25% 未经治疗的人会出现冠状动脉瘤 儿童KD，导致缺血性心脏病和心肌梗塞。当静脉注射免疫球蛋白时 (IVIG) 治疗将这一比例降低至 5%，高达 20% 的 KD 患者对 IVIG 具有耐药性，并且发生 IVIG 的风险更大 冠状动脉炎症。更好地了解导致疾病的免疫和病理机制 需要确定 KD 血管炎的发展，以确定更有效的 KD 治疗方法并预防长期的 KD 治疗。 由组织炎症和冠状动脉重塑引起的心血管后遗症。初步研究中 使用 KD 血管炎小鼠模型，我们发现与炎症反应和 IL-1 相关的基因 发炎的腹主动脉中信号传导上调。此外，Sirtuin 1 (SIRT1)（一种组蛋白）的表达 以其心脏保护功能而闻名的脱乙酰酶在小鼠发炎的腹主动脉中减少 在 KD 血管炎期间。因此，该 R01 应用的中心假设是 SIRT1 起着至关重要的作用 通过促进自噬/线粒体自噬来预防细菌配体诱导的 IL-1β 驱动的血管炎， 损害 NLRP3 炎性体激活和 IL-1β 产生。为了检验这个假设，我们将完成 具体目标如下：1）确定SIRT1的表达模式及其在细菌配体中的作用- 诱发 KD 血管炎；2) 确定 SIRT1 活性调节 LCWE 的机制 诱发KD血管炎。该提案具有非常高的转化潜力，并将确定化合物是否 已知激活和增加 SIRT1 活性将改善或减少川崎病的心血管病理。重要的是， 这些研究不仅将揭示 SIRT1 如何影响川崎病急性期的炎症反应 阶段，但也将深入了解 SIRT1 调节作为治疗干预措施的潜力，以预防 长期 KD 心血管并发症。此外，考虑到 IL-1 信号传导在 动脉粥样硬化，我们的研究结果可能为广泛的心血管疾病阐明新的治疗方向 疾病。