TRAF3IP2 in Ischemic Heart Disease

TRAF3IP2 在缺血性心脏病中的作用

基本信息

项目摘要

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TRAF 3 IP 2(TRAF 3相互作用蛋白2;也称为CIKS或Act 1)是一种衔接分子,可激活IKK和JNK,并通过诱导NF-B和AP-1应答性细胞因子、趋化因子、粘附分子和MMP表达来放大自身免疫和炎症反应。我们的初步数据表明,缺血/再灌注(IR)上调TRAF 3 IP 2在小鼠心脏的表达。值得注意的是,TRAF 3 IP 2基因缺失以心肌细胞特异性方式减弱心肌损伤(梗死面积)和IR后功能障碍(遗传方法)。此外,超声靶向TRAF 3 IP 2反义寡脱氧核苷酸显著减弱野生型小鼠IR后的心肌梗死,并且上级靶向其下游效应子p65和JNK 1(介入方法)。基于这些初步但关键的观察结果,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于TRAF 3 IP 2,导致IKK/NF-B和JNK/AP-1通路的激活,最终导致心肌IR损伤、功能障碍和不良重塑。我们的近期目标是了解TRAF 3 IP 2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述TRAF 3 IP 2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确定TRAF 3 IP 2在体内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TRAF 3 IP 2在体内IR诱导的不良重塑中是关键的具体目标3:通过(i)研究氧化应激和细胞因子诱导的TRAF 3 IP 2表达和调节的机制,和(ii)鉴定负责TRAF 3 IP 2与IL-18受体和MyD 88相互作用的结构基序。使用遗传和干预方法,这些新颖和创新的研究将确立TRAF 3 IP 2作为IR后心肌损伤、功能障碍和不良重塑的关键调节因子,并将其确定为IR损伤中比NF-B或JNK更好的治疗靶点。

项目成果

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Chandrasekar Bysani其他文献

Chandrasekar Bysani的其他文献

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{{ truncateString('Chandrasekar Bysani', 18)}}的其他基金

Role of novel RNA binding protein LARP6 in alcoholic cardiomyopathy
新型RNA结合蛋白LARP6在酒精性心肌病中的作用
  • 批准号:
    10593688
  • 财政年份:
    2023
  • 资助金额:
    --
  • 项目类别:
RECK in Adverse Cardiac Remodeling and Heart Failure
RECK 在不良心脏重构和心力衰竭中的应用
  • 批准号:
    10368301
  • 财政年份:
    2022
  • 资助金额:
    --
  • 项目类别:
RECK in Adverse Cardiac Remodeling and Heart Failure
RECK 在不良心脏重构和心力衰竭中的应用
  • 批准号:
    10655310
  • 财政年份:
    2022
  • 资助金额:
    --
  • 项目类别:
RECK regulation of NASH and fibrosis
RECK 对 NASH 和纤维化的调节
  • 批准号:
    10616763
  • 财政年份:
    2022
  • 资助金额:
    --
  • 项目类别:
TRAF3IP2 in Adverse Cardiac Remodeling and Heart Failure
TRAF3IP2 在不良心脏重塑和心力衰竭中的作用
  • 批准号:
    10266002
  • 财政年份:
    2018
  • 资助金额:
    --
  • 项目类别:
BLR&D Research Career Scientist Award Application
BLR
  • 批准号:
    10047289
  • 财政年份:
    2017
  • 资助金额:
    --
  • 项目类别:
BLRD Research Career Scientist Award Application
BLRD 研究职业科学家奖申请
  • 批准号:
    10587293
  • 财政年份:
    2017
  • 资助金额:
    --
  • 项目类别:
BLR&D Research Career Scientist Award Application
BLR
  • 批准号:
    10293563
  • 财政年份:
    2017
  • 资助金额:
    --
  • 项目类别:
TRAF3IP2 in Ischemic Heart Disease
TRAF3IP2 在缺血性心脏病中的作用
  • 批准号:
    9339531
  • 财政年份:
    2014
  • 资助金额:
    --
  • 项目类别:
TRAF3IP2 in Ischemic Heart Disease
TRAF3IP2 在缺血性心脏病中的作用
  • 批准号:
    8846473
  • 财政年份:
    2014
  • 资助金额:
    --
  • 项目类别:

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