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 25% 未经治疗的患者可能会出现长期心血管后遗症。儿童KD，同时静脉注射免疫球蛋白导致缺血性心脏病和心肌梗塞。 (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 的风险更大更好地了解导致冠状动脉炎症的免疫和病理机制。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。初步研究表明，组织炎症和冠状动脉重塑会导致心血管后遗症。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的信号传导上调此外，组蛋白 Sirtuin 1 (SIRT1) 的表达也上调。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因此，该 R01 应用的中心假设是 SIRT1 发挥着关键作用。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 产生为了检验这一假设，我们将完成以下实验。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 血管炎和 2) 确定 SIRT1 活性调节 LCWE 的机制诱导的 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有效。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学。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，以预防此外，考虑到 IL-1 信号传导在长期 KD 心血管并发症中的作用。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。