TRAF3IP2 in Ischemic Heart Disease

TRAF3IP2 在缺血性心脏病中的作用

• 批准号: 8736118
• 负责人: Chandrasekar Bysani
• 金额: --
• 依托单位: SOUTHEAST LOUISIANA VETERANS HEALTH CARE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8736118
• 关键词: Address; Apoptotic; Attenuated; Autoimmune Process; Autoimmune Responses; Binding; Cardiac Myocytes; Cause of Death; Cell Adhesion Molecules; Cells; Cessation of life; Clinical; Complex; Cytoplasm; Data; Depressed mood; Disease; Free Radicals; Functional disorder; Gene Deletion; Gene Expression; Generations; Genetic; Goals; Healthcare Systems; Heart; Hospitalization; Hypoxia; In Vitro; Induction of Apoptosis; Infarction; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-18; Intervention; Ischemia; JUN gene; Lead; MAPK8 gene; MMP9 gene; Matrix Metalloproteinases; Mediating; Military Personnel; Modeling; Molecular; Morbidity - disease rate; Mus; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardial dysfunction; Nuclear Translocation; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Peptides; Phosphorylation; Phosphotransferases; Population; Proteins; Regulation; Reperfusion Injury; Reperfusion Therapy; Reporting; Role; Serine; Signal Transduction; TNF receptor-associated factor 3; TNFRSF5 gene; Therapeutic Intervention; Time; Tissues; Transcription Factor AP-1; Transcriptional Regulation; Ultrasonography; United States; Veterans; Wild Type Mouse; Wit; Woman; base; chemokine; clinically relevant; cytokine; immune activation; in vivo; inhibitor/antagonist; innovation; men; mortality; multicatalytic endopeptidase complex; novel strategies; p65; promoter; protein B; public health relevance; receptor; therapeutic target; transcription factor; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Ischemic heart disease (IHD) is a leading cause of death for both men and women in the United States, and is one of the most frequent indications for hospitalization within the Veterans Health Care System. The E3 ubiquitin ligase TRAF3IP2 (TRAF3-interacting protein 2; also known as CIKS or Act1) is an adapter molecule that activates both IKK and JNK, and amplifies autoimmune and inflammatory responses by inducing NF-B- and AP-1-responsive cytokine, chemokine, adhesion molecule and MMP expression. Our preliminary data show that ischemia/reperfusion (IR) upregulates TRAF3IP2 expression in the mouse heart. Notably, TRAF3IP2 gene deletion in a cardiomyocyte-specific manner blunts myocardial injury (infarct size) and dysfunction post-IR (genetic approach). Further, an ultrasound-targeted TRAF3IP2 antisense oligodeoxynucleotide markedly attenuates myocardial infarct post-IR in wild type mice, and was superior to targeting its downstream effectors p65 and JNK1 (interventional approach). Based on these preliminary but critical observations, our central hypothesis is that IR-induced oxidative stress and cytokine expression converge on TRAF3IP2, resulting in the activation of IKK/NF-B and JNK/AP-1 pathways that ultimately lead to myocardial IR injury, dysfunction, and adverse remodeling. Our immediate goal is to understand the expression, regulation and role of TRAF3IP2 in IR injury, and develop strategies to target its expression in a clinically relevant time frame. Our long-term objective is to delineate the causal role of TRAF3IP2 in other models of myocardial injury and inflammation. To address our HYPOTHESIS, the following specific aims are proposed: Specific Aim 1: Define the critical role of TRAF3IP2 in IR-induced myocardial injury and dysfunction in vivo using genetic and interventional approaches Specific Aim 2: Demonstrate that TRAF3IP2 is critical in IR-induced adverse remodeling in vivo Specific Aim 3: Discover potential targets for intervention by (i) Investigating the mechanisms of oxidative stress and cytokine induced TRAF3IP2 expression and regulation, and (ii) Identifying the structural motifs responsible for TRAF3IP2 interaction wit the IL-18 receptor and MyD88. Using both genetic and interventional approaches, these novel and innovative studies will establish TRAF3IP2 as a pivotal regulator of myocardial injury, dysfunction, and adverse remodeling post-IR, and identify it as a better therapeutic target than either NF-B or JNK in IR injury.

描述（由申请人提供）： 缺血性心脏病 (IHD) 是美国男性和女性死亡的主要原因，也是退伍军人医疗保健系统中最常见的住院适应症之一。 E3 泛素连接酶 TRAF3IP2（TRAF3 相互作用蛋白 2；也称为 CIKS 或 Act1）是一种接头分子，可激活 IKK 和 JNK，并通过诱导 NF-B 和 AP-1 反应性细胞因子来放大自身免疫和炎症反应。趋化因子、粘附分子和 MMP 表达。我们的初步数据表明，缺血/再灌注 (IR) 上调小鼠心脏中 TRAF3IP2 的表达。值得注意的是，以心肌细胞特异性方式缺失 TRAF3IP2 基因可以减轻心肌损伤（梗死面积）和 IR 后功能障碍（遗传方法）。此外，超声靶向 TRAF3IP2 反义寡脱氧核苷酸可显着减轻野生型小鼠 IR 后的心肌梗塞，并且优于靶向其下游效应器 p65 和 JNK1（介入方法）。基于这些初步但关键的观察，我们的中心假设是IR诱导的氧化应激和细胞因子表达集中在TRAF3IP2上，导致IKK/NF-B和JNK/AP-1途径的激活，最终导致心肌IR损伤，功能障碍和不良重塑。我们的近期目标是了解 TRAF3IP2 在 IR 损伤中的表达、调节和作用，并制定在临床相关时间范围内靶向其表达的策略。我们的长期目标是描绘 TRAF3IP2 在其他心肌损伤和炎症模型中的因果作用。为了解决我们的假设，提出了以下具体目标： 具体目标 1：使用遗传和介入方法在体内定义 TRAF3IP2 在 IR 诱导的心肌损伤和功能障碍中的关键作用 具体目标 2：证明 TRAF3IP2 在 IR 诱导的心肌损伤和功能障碍中至关重要体内不良重塑 具体目标 3：通过 (i) 研究氧化应激和细胞因子诱导的 TRAF3IP2 表达和调节的机制，发现潜在的干预靶点，以及(ii)鉴定负责TRAF3IP2与IL-18受体和MyD88相互作用的结构基序。这些新颖和创新的研究将使用遗传和介入方法，将 TRAF3IP2 确立为 IR 后心肌损伤、功能障碍和不良重塑的关键调节因子，并确定其作为 IR 损伤中比 NF-B 或 JNK 更好的治疗靶点。