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: 10427424
• 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/10427424
• 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; antagonist; 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; translational potential; 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