TRAF3IP2 in Ischemic Heart Disease

描述(由申请人提供)： 在美国，缺血性心脏病(IHD)是导致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指征之一。E3泛素连接酶TRAF3IP2(TRAF3相互作用蛋白2，也称为CIKS或Act1)是一种适配分子，可同时激活IKK和JNK，并通过诱导NF-B和AP-1应答的细胞因子、趋化因子、黏附分子和基质金属蛋白酶的表达来放大自身免疫和炎症反应。我们的初步数据显示，缺血/再灌注(IR)上调了小鼠心脏中TRAF3IP2的表达。值得注意的是，心肌细胞特有的TRAF3IP2基因缺失可以钝化IR后的心肌损伤(梗塞范围)和功能障碍(遗传方法)。此外，超声靶向的TRAF3IP2反义寡核苷酸显著减轻野生型小鼠IR后的心肌梗死，并且优于靶向其下游效应的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会聚在TRAF3IP2上，导致IKK/NF-B和JNK/AP-1通路的激活，最终导致心肌IR损伤、功能障碍和不利的重构。我们的近期目标是了解TRAF3IP2在IR损伤中的表达、调节和作用，并开发在临床相关的时间框架内靶向其表达的策略。我们的长期目标是阐明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，提出了以下特定目标：特定目标1：使用遗传学和干预方法确定TRAF3IP2在IR诱导的在体心肌损伤和功能障碍中的关键作用特定目标2：证明TRAF3IP2在IR诱导的体内不利重构中起关键作用特定目标3：通过(I)研究氧化应激和细胞因子诱导TRAF3IP2表达和调节的机制，以及(Ii)确定TRAF3IP2与IL-18受体和MyD88相互作用的结构基序，发现潜在的干预靶点。利用遗传学和介入方法，这些新颖和创新的研究将确立TRAF3IP2作为IR后心肌损伤、功能障碍和不良重构的关键调节因子，并确定它是比NF-B或JNK更好的IR损伤的治疗靶点。

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.