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

基本信息

批准号：
10657443
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
项目类别：
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/10657443
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 IL1R1 gene 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 Lesion Ligands Mediating Modeling Molecular Molecular Mimicry Monoclonal Antibodies Mucocutaneous Lymph Node Syndrome Mus Myocardial Infarction Myocardial Ischemia Myocarditis Pathogenesis Pathologic Pathway interactions Patients Pattern Phase Play Prediction of Response to Therapy Prevention Process Production Recycling Resistance Risk Role SIRT1 gene Signal Transduction Superantigens Testing Therapeutic Therapeutic Intervention Tissues Vascular remodeling Vasculitis Whole Blood abdominal aorta anakinra antagonist cardioprotection coronary arteritis coronary fibrosis experimental study gene discovery high risk immune cell infiltrate improved infection risk insight mitochondrial autophagy mouse model novel novel therapeutics overexpression pharmacologic prevent protective effect response stem therapeutically effective transcriptome translational potential vascular inflammation vascular injury

项目摘要

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）是美国儿童获得心脏病的主要原因，是急性被认为是感染性病因的高热疾病和全身血管炎，导致冠状动脉动脉瘤并可能导致长期心血管后遗症。冠状动脉瘤在未经治疗的25％ KD儿童，导致缺血性心脏病和心肌梗塞。而静脉免疫球蛋白（IVIG）治疗降低到5％，多达20％的KD患者具有IVIG耐药性，并且具有更大的风险冠状动脉炎症。更好地了解导致的免疫和病理机制需要开发KD血管炎，以确定更有效的KD疗法并防止长期由组织注射和冠状动脉重塑的心血管后遗症。在初步研究中使用KD血管炎的鼠模型，我们发现与炎症反应有关的基因和IL-1 发炎的腹主动脉更新信号。此外，Sirtuin 1（SIRT1）的表达，一个组蛋白脱乙酰基酶以其心脏保护功能而闻名，在发炎的小鼠腹主动脉中降低在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/线粒体来预防配体配体诱导的IL-1β驱动的血管炎会损害NLRP3炎性体激活和IL-1β产生。为了检验这一假设，我们将完成以下特定目的：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KD血管炎。该提案具有很高的翻译潜力，并将确定是否化合物已知会激活和增加SIRT1活性将改善或减少KD的心血管病理。重要的是，这些研究不仅会阐明SIRT1在KD急性期间如何影响炎症反应阶段，但还将洞悉SIRT1调制的潜力作为治疗干预措施长期KD心血管并发症。此外，鉴于IL-1信号在动脉粥样硬化，我们的发现可能会照亮各种心血管的新型热方向疾病。