BLR&D Research Career Scientist Award Application

BLR

• 批准号: 10047289
• 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: 2017
• 资助国家: 美国
• 起止时间: 2017-10-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10047289
• 关键词: Affect; Aldosterone; Angiotensin II; Atherosclerosis; Award; Binding; Bioinformatics; Biopsy; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cell Death; Centers for Disease Control and Prevention (U.S.); Characteristics; Chronic Disease; Collaborations; Collagen; Colorado; Complement Factor H; Critical Pathways; Deposition; Development; Diabetes Mellitus; Disease Progression; Endothelial Cells; Epidermal Growth Factor Receptor; Etiology; Family member; Fibrillar Collagen; Fibroblasts; Florida; Functional disorder; Funding; GPI Membrane Anchors; Gene Deletion; Genes; Genetic Transcription; Goals; Healthcare; Healthcare Systems; Heart; Heart Diseases; Heart Hypertrophy; Heart Injuries; Heart failure; Human; Hypertension; Hypertrophy; IL6ST gene; In Vitro; Infarction; Inflammation; Inflammatory; Interleukin-1; Interleukin-1 Receptors; Interleukin-1 beta; Interleukin-17; Interleukin-18; Interleukin-2; Interleukins; Intervention Studies; Isoproterenol; Knock-in Mouse; Knock-out; Lead; MAP Kinase Gene; MAPK8 gene; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Mediating; Mediator of activation protein; Membrane; Messenger RNA; Microbubbles; Mission; Modeling; Molecular; Morbidity - disease rate; Mutate; Myocardial; Myocardial Ischemia; Myocardial dysfunction; Nodal; Obesity; Oxidative Stress; Pathogenesis; Pathologic; Pathology; Patient-Focused Outcomes; Patients; Pharmacology; Pilot Projects; Play; Population; Problem Solving; Progressive Disease; Proteins; Publications; RNA; RNA-Binding Proteins; Recombinant Interleukins; Reperfusion Injury; Reporting; Research; Research Personnel; Ribonucleoproteins; Role; Scientist; Services; Signal Transduction; Signal Transduction Pathway; Smoking; Survivors; System; TLR4 gene; TNF receptor-associated factor 3; Therapeutic; Time; Tissues; Transcription Factor AP-1; Transgenic Mice; Ultrasonography; United States National Center for Health Statistics; Universities; Ventricular Remodeling; Veterans; aortic valve replacement; career; cell type; chemokine; comorbidity; coronary fibrosis; cysteine rich protein; cytokine; efficacy testing; gain of function; gene therapy; glycoprotein 130; improved; improved functioning; in vivo; interleukin-1 receptor accessory protein; interleukin-18 receptor; ischemic injury; loss of function; migration; military veteran; mortality; mouse model; myocardial injury; neutralizing antibody; new therapeutic target; overexpression; p38 Mitogen Activated Protein Kinase; pressure; receptor; sex; siRNA delivery; stem; therapeutic target; tissue injury; transcription factor; ubiquitin ligase

ABSTRACT Nearly 63 million people (20% of the US population) are eligible for VA benefits and services because they are veterans, family members or survivors of veterans. Cardiovascular diseases (CVD) contribute to significant morbidity and mortality of the military veterans and civilians (CDC/National Center for Health Statistics). I have been associated with VA and non-VA funded clinician-scientists and basic researchers for the past 20 years. I am also a VA funded investigator. The overall focus of my research as a VA funded scientist is to investigate the causal role of inflammation, inflammatory cytokines and chemokines, and NF-κB activation in CVD. Since inflammation is a critical component in the pathogenesis of CVD, and CVD are the major contributing factors for morbidity and mortality within both military veteran and civilian populations of both sexes, my studies are highly relevant to the VA mission. Furthermore, hypertension, diabetes, obesity and smoking predispose veterans and civilians alike to CVD, my ongoing studies are timely and critical in further understanding the pathophysiology of these chronic diseases. Using the most promising research strategies and problem-solving approaches, my goal is to identify newer therapeutic targets in CVD. TRAF3 Interacting Protein 2 (TRAF3IP2) is a cytoplasmic adapter molecule and an upstream regulator of at least three major signal transduction pathways that are known to play a pathological role in ischemic cardiac diseases. TRAF3IP2 activates IKK/NF-κB, JNK/AP-1 and p38 MAPK, and induces the expression of multiple cytokines and chemokines with negative myocardial inotropic effects. It also regulates the expression of collagens and MMPs. TRAF3IP2 is a critical intermediate in IL-17 signaling, another proinflammatory cytokine involved in ischemic cardiac disease. Our preliminary results show that TRAF3IP2 also plays a role in IL-18 signaling. In fact, we found that TRAF3IP2 binds the TIR (The Toll/Il-1 Receptor)-domain containing IL-18 receptor via binding motifs that appear to be different from those responsible for TRAF3IP2/IL-17R binding. Bioinformatics revealed that TRAF3IP2 could also associate with IL-1RacP (Interleukin 1 Receptor Accessory Protein), an IL- 1β receptor. We previously reported that TRAF3IP2 also plays a role in LPS/Toll-like receptor 4-mediated cardiomyocyte contractile dysfunction, suggesting that targeting TRAF3IP2 could blunt IL-17, IL-18, IL-1 and LPS signaling, all of which contribute causally to various cardiac pathologies, including cardiac ischemic injury. Utilizing both in vivo (genetic and interventional) and in vitro (cardiomyocytes and cardiac fibroblasts) models, my ongoing studies are examining the relationship between TRAF3IP2, inflammation and heart failure (HF) of ischemic/non-ischemic origin in vivo and the underlying molecular mechanisms in vitro. My long-term goal is to develop therapeutic strategies to inhibit TRAF3IP2 expression. Recently, we targeted TRAF3IP2 by UTMD (ultrasound-targeted microbubble destruction)-mediated delivery of AS-ODN into LV, and demonstrated significant reduction in cardiac TRAF3IP2 expression, myocardial injury (infarct size), adverse remodeling and HF development. In addition, my ongoing studies are focused on unraveling the roles of the RNA binding protein Larp6 (stimulates collagen I and III expression) and the membrane-anchored protein RECK (inhibits multiple MMPs, ADAMs, EGFR, uPA and gp130) in adverse cardiac remodeling and HF development. !!

抽象的 近6300万人（占美国人口的20％）有资格获得VA福利和服务，因为 他们是退伍军人，家庭成员或退伍军人的幸存者。心血管疾病（CVD）有助于 军事退伍军人和平民的大量发病和死亡（CDC/国家卫生中心 统计数据）。我与VA和非VA资助的临床科学家和基础研究人员有关 过去20年。我也是VA资助的调查员。我作为VA资助​​的研究的总体重点 科学家将研究感染，炎性细胞因子和趋化因子和NF-κB的因果作用 CVD激活。由于炎症是CVD发病机理中的关键成分，因此CVD是 两者的退伍军人和平民人口中发病和死亡的主要因素 性别，我的研究与VA任务高度相关。此外，高血压，糖尿病，肥胖和 吸烟倾向的退伍军人和平民都对CVD进行 了解这些慢性疾病的病理生理学。使用最有前途的研究策略 和解决问题的方法，我的目标是确定CVD中的新治疗靶标。 TRAF3相互作用 蛋白2（TRAF3IP2）是细胞质适配器分子和至少三个主要的上游调节剂 已知在缺血性心脏病中起病理作用的信号转导途径。 TRAF3IP2激活IKK/NF-κB，JNK/AP-1和P38 MAPK，并诱导多种细胞因子的表达 和趋化因子，具有阴性心肌肌力作用。它还调节胶原蛋白的表达和 MMP。 TRAF3IP2是IL-17信号传导中的关键中间体，另一种参与的促炎细胞因子 缺血性心脏病。我们的初步结果表明，TRAF3IP2在IL-18信号传导中也起作用。在 事实，我们发现TRAF3IP2结合TIR（TOLL/IL-1受体） - 含有IL-18受体的域 - 通过 与负责TRAF3IP2/IL-17R结合的结合基序似乎不同。生物信息学 揭示Traf3ip2也可以与IL-1RACP（白介素1受体辅助蛋白）相关联 1β受体。我们先前报道说TRAF3IP2在LPS/Toll样受体4介导的 心肌细胞收缩功能障碍，表明靶向TRAF3IP2可以钝化IL-17，IL-18，IL-1和 LPS信号传导，不幸的是，所有这些都对各种心脏病理，包括心脏缺血性损伤。 利用体内（遗传和介入）和体外（心肌细胞和心脏成纤维细胞）模型， 我正在进行的研究正在研究TRAF3IP2，炎症和心力衰竭（HF）之间的关系 体内缺血/非缺血性起源和体外的潜在分子机制。我的长期目标是 制定理论策略来抑制TRAF3IP2表达。最近，我们针对UTMD的TRAF3IP2 （超声靶向的微泡破坏）介导的AS-ODN递送到LV中，并证明 心脏TRAF3IP2表达，心肌损伤（梗塞大小），不良重塑和 HF开发。此外，我正在进行的研究集中于揭开RNA结合的作用 蛋白LARP6（刺激胶原I和III表达）和膜锚定的蛋白质RECK（抑制） 多个MMP，Adams，EGFR，UPA和GP130）提前心脏重塑和HF开发。 !!