Interleukin-18 and post infarct myocardial remodeling

Interleukin-18 与梗死后心肌重塑

基本信息

批准号：
7686633
负责人：
Chandrasekar Bysani
金额：
--
依托单位：
SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7686633
关键词：
70-kDa Ribosomal Protein S6 Kinases Activation Analysis Acute Acute myocardial infarction Address Adrenergic beta-Antagonists Angiotensin-Converting Enzyme Inhibitors Apoptosis Autoimmune Responses Biochemical Cardiac Cardiac Myocytes Cell Adhesion Molecules Cell Death Cells Cessation of life Chronic Complex Congestive Heart Failure Data Deposition Deterioration Development Dilatation - action Disease Down-Regulation Extracellular Matrix Failure Fibroblasts Fibrosis Genes Goals Growth Factor Health Hospitalization Human Hypertrophy In Vitro Incidence Infarction Inflammatory Inflammatory Response Injury Interleukin-18 Interleukin-6 Knock-out Knockout Mice Left Ventricular Hypertrophy Left Ventricular Remodeling Measures Mediating Military Personnel Molecular Morbidity - disease rate Mus Myocardial Myocardial Infarction Myocardium Outcome PTEN gene Pathologic Processes Pathology Patient Care Patients Performance Phase Phenotype Play Population Process Publishing Reaction Regulation Reporting Role Signal Transduction Therapeutic Tissues Transgenic Mice Ventricular Ventricular Remodeling Veterans abstracting base chemokine cytokine design fetal gain of function human TSC2 protein immune activation improved in vivo inflammatory marker injured innovation interleukin-18 receptor loss of function migration mortality myocardial infarct sizing novel overexpression therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Abstract Acute myocardial infarction (MI) is a major cause of morbidity and mortality in the US, within both the veteran and civilian populations. Proinflammatory cytokines are known to play a central role in post-MI tissue injury, remodeling and failure. Interleukin-18 (IL-18) is an inducible proinflammatory cytokine, and amplifies many autoimmune and inflammatory responses via the induction of other cytokines, chemokines, and adhesion molecules. Our studies, both published and preliminary, clearly indicate that IL-18 participates in pathological remodeling post-MI. Based on these findings, our central hypothesis is that IL-18 plays a pivotal role in myocardial remodeling post-MI by promoting cardiomyocyte apoptosis and hypertrophy, by regulating the deposition and composition of extracellular matrix, and by inducing fibroblast proliferation and fibrosis. While our long-term objective is to delineate the precise pathological role of proinflammatory cytokines in myocardial remodeling, our immediate goal is to establish an etiological role for IL-18 in post-MI cardiac remodeling and failure. To address our central hypothesis, three specific aims are proposed: In Specific Aim 1, we will define the causal role of IL-18 in vivo in post-infarct cardiac remodeling and failure using wild-type, cardiac-specific IL-18 knockout, and cardiac-restricted overexpressor (IL-18 transgenic) mice. In Specific Aim 2, we will characterize the effects of IL-18 on cell death and hypertrophy in cardiomyocytes in vitro. In Specific Aim 3, we will identify the IL-18-dependent molecular mechanisms responsible for migration and proliferation of cardiac fibroblast in vitro. These novel and innovative studies will integrate functional, molecular, biochemical and histological approaches in order to address the central hypothesis. Our proposed in vitro studies in cardiomyocytes and cardiac fibroblasts will help refine and further support our in vivo studies by delineating the molecular mechanisms that connect IL-18 signaling to this maladaptive phenotype. Completion of our proposed studies will provide a better understanding of the pathobiological processes involved in myocardial injury and remodeling post-MI, establish IL-18 as a causative factor, and thus identify it as a potential therapeutic target in post-MI cardiac injury and remodeling. PUBLIC HEALTH RELEVANCE: Narrative Acute myocardial infarction (MI) is a major cause of morbidity and mortality in the US, within both the military veteran and civilian populations. Post-infarct myocardial remodeling, hypertrophy and its transition to congestive heart failure are important diseases, resulting in quarter million deaths and one million hospitalizations annually in the US. Understanding the molecular mechanisms underlying these pathological processes will help us design more effective therapeutic strategies to better care for these patients. The primary goal of this proposal is to better understand the role of inflammatory cytokines, interleukin-18 in particular, in post-infarct myocardial injury, remodeling and failure.

描述（由申请人提供）：抽象急性心肌梗塞（MI）是美国和平民在美国发病率和死亡率的主要原因。众所周知，促炎细胞因子在MI组织损伤，重塑和衰竭中起着核心作用。白介素-18（IL-18）是一种可诱导的促炎细胞因子，并通过诱导其他细胞因子，趋化因子和粘附分子来放大许多自身免疫性和炎症反应。我们的研究均发表和初步，清楚地表明IL-18参与了MI后的病理重塑。基于这些发现，我们的中心假设是IL-18通过调节细胞外基质的沉积和组成，通过促进心肌细胞凋亡和肥大，在MI后MI中起关键作用，并诱导成纤维细胞增殖和纤维化。尽管我们的长期目标是描述促炎细胞因子在心肌重塑中的确切病理作用，但我们的近期目标是确定IL-18在MI后心脏重塑和失败中的病因学作用。为了解决我们的中心假设，提出了三个具体目的：在特定的目标1中，我们将使用野生型，心脏特异性IL-18敲除和心脏特异性IL-18敲除和心脏限制性过表达（IL-18 Transgenic）小鼠的因素在体内进行体内的因果作用。在特定目标2中，我们将表征IL-18对体外心肌细胞细胞死亡和肥大的影响。在特定目标3中，我们将确定导致心脏成纤维细胞在体外迁移和增殖的IL-18依赖性分子机制。这些新颖的创新研究将整合功能，分子，生化和组织学方法，以解决中心假设。我们提出的在心肌细胞和心脏成纤维细胞中的体外研究将通过描述将IL-18信号传导与这种不良适应性表型联系起来的分子机制，从而有助于完善和进一步支持我们的体内研究。我们提出的研究的完成将更好地理解心肌损伤和重塑后涉及的病理生物学过程，将IL-18建立为病因，从而将其确定为MI后心脏损伤和重塑的潜在治疗靶标。公共卫生相关性：叙事急性心肌梗塞（MI）是美国退伍军人和平民在美国发病率和死亡率的主要原因。感染后心肌重塑，肥大及其向充血性心力衰竭的过渡是重要的疾病，每年在美国造成25万人死亡和一百万个住院。了解这些病理过程的分子机制将有助于我们设计更有效的治疗策略，以更好地护理这些患者。该提案的主要目的是更好地了解炎性细胞因子，尤其是白介素-18的作用，尤其是在染色后心肌损伤中，重塑和衰竭。