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
• 负责人: Chandrasekar Bysani
• 金额: --
• 依托单位: HARRY S. TRUMAN MEMORIAL VA HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10266002
• 关键词: Age-Years; Aortic Valve Stenosis; Attenuated; Autoimmune; Biochemical; Cardiac; Cardiac Myocytes; Caring; Cell Adhesion Molecules; Cessation of life; Congestive Heart Failure; Data; Deposition; Development; Disease; Effectiveness; Enzymes; Etiology; Extracellular Matrix; Failure; Fibroblasts; Fibrosis; Functional disorder; Gene Deletion; Genes; Goals; Growth; Health; Healthcare Systems; Heart; Heart failure; Histologic; Hospitalization; Human; Hypertension; Hypertrophy; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Intervention; Knock-out; Knockout Mice; Left; Left Ventricular Hypertrophy; MAPK8 gene; Matrix Metalloproteinases; Mediating; Mediator of activation protein; Medicare; Microbubbles; Molecular; Molecular Analysis; Mus; Myocardial; N-terminal; NF-kappa B; Oxidative Stress; Pathogenesis; Pathologic; Pathologic Processes; Patient Care; Patients; Pharmacology; Phosphotransferases; Play; Population; Production; Proteins; Publishing; Reactive Oxygen Species; Regulation; Reporting; Role; Secondary to; Signal Pathway; Signal Transduction; Small Interfering RNA; TNF receptor-associated factor 3; Techniques; Testing; Therapeutic; Tissues; Transcription Factor AP-1; Transgenic Mice; Ultrasonography; United States Department of Veterans Affairs; Ventricular; Ventricular Remodeling; Veterans; Wild Type Mouse; base; cell type; chemokine; constriction; curative treatments; cytokine; design; experience; experimental study; gene therapy; hospital readmission; immune activation; inhibitor/antagonist; innate immune pathways; innovation; lifetime risk; migration; military veteran; mortality; mouse model; new therapeutic target; novel; novel therapeutics; older patient; overexpression; pre-clinical; pressure; preventive intervention; therapeutic target; therapeutically effective

According to the US Department of Veterans Affairs, heart failure (HF) and associated complications are one of the main reasons for hospital readmissions and death in the Veterans Health Care System. In fact, above 40 years of age, the lifetime risk of developing HF is one in 5, and readmissions occur within 30 days of discharge in 20% of patients older than 65 in the Medicare population and the Veterans Health Care System. Together, these healthcare systems incurred nearly $37.2 billions for HF care in 2009. A substantial number of patients develop severe LVH secondary to pressure overload (e.g., hypertension, aortic valve stenosis), and experience episodic severe congestive HF, hospitalization, and increased mortality. Pressure overload-induced left ventricular hypertrophy and transition to heart failure involves activation of both inflammatory and innate immune pathways, with the sustained activation of Nuclear factor kappa B (NF-κB) and Activator Protein 1 (AP-1) playing a key role in their pathogenesis. Our studies, both published and preliminary, clearly indicate that the cytoplasmic adapter molecule TRAF3IP2 (TRAF3 Interacting Protein 2) plays a causal role in the pathogenesis of pressure overload-induced myocardial hypertrophy, fibrosis and dysfunction in a pre-clinical mouse model. Our pilot experiments also demonstrate TRAF3IP2 expression is increased in both hypertrophic and failing human hearts. Based on these critical findings, our central hypothesis is that TRAF3IP2 plays a pivotal role in pressure overload-induced adverse cardiac remodeling and heart failure development by inducing the activation of critical signaling intermediates like IκB kinase (IKK)/NF-κB and c-Jun N-terminal kinase (JNK)/AP-1, increased expression and secretion of pro-inflammatory and pro-fibrotic mediators, and excessive production and deposition of altered extracellular matrix, resulting ultimately in adverse cardiac remodeling and contractile dysfunction. While our long-term goals are to understand the molecular mechanisms involved in the pathophysiology of myocardial hypertrophy and its transition to heart failure, and to identify novel therapeutic target(s) for intervention and treatment, our immediate goals are to determine the etiological role of TRAF3IP2 in the pathogenesis of pressure overload-induced adverse cardiac remodeling and heart failure development, and to develop an interventional strategy to target its expression in the heart. To test our central hypothesis, three specific aims are proposed: In Specific Aim 1, we will define the causal role of TRAF3IP2 in pressure overload-induced myocardial hypertrophy, fibrosis and failure using inducible cardiomyocyte-specific TRAF3IP2 knockout and overexpressor mice. In Specific Aim 2, we will delineate the causal role of TRAF3IP2 in pressure overload-induced LVH, fibrosis and failure using fibroblast-specific TRAF3IP2 knockout mice. In Specific Aim 3, we will establish the effectiveness of UTMD (ultrasound-targeted microbubble destruction)-mediated silencing of TRAF3IP2 to attenuate pressure overload-induced LVH, fibrosis and failure in wild type mice. These novel and innovative studies utilizing cell type-specific gene-altered mouse models and UTMD- mediated preventative and curative interventional approach, as well as state-of-the art techniques (functional, biochemical, histological, and molecular analyses) will evaluate TRAF3IP2 as a central causative factor, and thus a potential therapeutic target in pressure overload-induced adverse cardiac remodeling and heart failure development.

根据美国退伍军人事务部，心力衰竭（HF）和相关并发症 是退伍军人医疗保健系统中再次入院和死亡的主要原因之一。事实上， 在40岁以上，发生HF的终生风险为五分之一，并且在30天内发生再入院。 在医疗保险人群和退伍军人医疗保健系统中，65岁以上的患者中有20%出院。 2009年，这些医疗保健系统在HF护理方面总共花费了近372亿美元。相当数量的 患者发展出继发于压力超负荷的严重LVH（例如，高血压、主动脉瓣狭窄），以及 出现偶发性重度充血性HF、住院和死亡率增加。 压力超负荷诱导的左心室肥厚和向心力衰竭转变涉及激活 炎症和先天性免疫途径，持续激活核因子κ B (NF-κB）和激活蛋白1（AP-1）在其发病机制中起关键作用。 我们的研究，无论是已发表的还是初步的，都清楚地表明细胞质衔接分子 TRAF 3 IP 2（TRAF 3 Interacting Protein 2）在压力超负荷诱导的心肌梗死的发病机制中起着重要作用。 心肌肥大、纤维化和功能障碍。我们的试点实验也 证明TRAF 3 IP 2表达在肥大和衰竭的人类心脏中均增加。基于这些 关键的发现，我们的中心假设是TRAF 3 IP 2在压力过载诱导的 通过诱导关键信号的激活而导致不利的心脏重塑和心力衰竭的发展 中间体如IκB激酶（IKK）/NF-κB和c-Jun N-末端激酶（JNK）/AP-1，增加表达， 促炎和促纤维化介质的分泌，以及改变的 细胞外基质，最终导致不利的心脏重塑和收缩功能障碍。虽然我们的 长期的目标是了解参与心肌梗死病理生理学的分子机制， 肥大及其向心力衰竭的转变，并鉴定用于干预的新的治疗靶点， 治疗，我们的直接目标是确定TRAF 3 IP 2的发病机制中的病因作用， 压力超负荷引起的不良心脏重塑和心力衰竭的发展，并发展为一种 介入策略靶向其在心脏中的表达。为了验证我们的核心假设，三个具体目标 建议： 在具体目标1中，我们将定义TRAF 3 IP 2在压力超负荷诱导的心肌梗死中的因果作用。 使用可诱导的心肌细胞特异性TRAF 3 IP 2敲除和过表达的肥大、纤维化和衰竭 小鼠 在具体目标2中，我们将描述TRAF 3 IP 2在压力超负荷诱导的LVH中的因果作用， 使用成纤维细胞特异性TRAF 3 IP 2敲除小鼠的纤维化和衰竭。 在具体目标3中，我们将确定UTMD（超声靶向微泡）的有效性 破坏）介导的TRAF 3 IP 2沉默以减轻压力超负荷诱导的LVH、纤维化和衰竭 在野生型小鼠中。 这些新的和创新的研究利用细胞类型特异性基因改变的小鼠模型和UTMD- 介导的预防性和治疗性干预方法，以及最先进的技术（功能性， 生物化学、组织学和分子分析）将评估TRAF 3 IP 2作为中心致病因素， 因此，在压力超负荷诱导的不良心脏重塑和心力衰竭中， 发展