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， 发热性疾病和全身性血管炎，被认为是引起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%未经治疗的患者会发生冠状动脉瘤。 KD患儿，导致缺血性心脏病和心肌梗死。而静脉注射免疫球蛋白 IVIG治疗将这一比率降低至5%，高达20%的KD患者是IVIG耐药的，并且具有更大的风险。 冠状动脉炎症更好地理解导致免疫和病理机制， 需要KD血管炎的发展来确定更有效的KD治疗方法并预防长期的KD并发症。 心血管后遗症源于组织炎症和冠状动脉重塑。在初步研究中 使用KD血管炎的小鼠模型，我们发现炎症反应和IL-1相关基因 信号在发炎的腹主动脉中上调。此外，表达Sirtuin 1（SIRT 1），一种组蛋白， 已知具有心脏保护功能的去乙酰化酶在小鼠的腹主动脉发炎中减少 川崎病血管炎的症状因此，该R 01应用的中心假设是SIRT 1在 通过促进自噬/线粒体自噬预防细菌配体诱导的IL-1β驱动的血管炎， 损害NLRP 3炎性体活化和IL-1β产生。为了验证这一假设，我们将完成 以下具体目的：1）确定SIRT 1的表达模式及其在细菌配体- 诱导的KD血管炎和2）确定SIRT 1活性调节LCWE的机制。 诱导KD血管炎。该提议具有非常高的翻译潜力，将决定化合物 已知激活和增加SIRT 1活性将改善或减少KD的心血管病理。重要的是， 这些研究不仅揭示了SIRT 1如何影响KD急性期的炎症反应， 但也将提供对SIRT 1调节作为治疗干预的潜力的深入了解，以防止 KD长期心血管并发症此外，鉴于IL-1信号转导在 动脉粥样硬化，我们的研究结果可能会照亮新的治疗方向，为广泛的心血管疾病 疾病