BLR&D Research Career Scientist Award Application

摘要 近6300万人(占美国人口的20%)有资格享受退伍军人管理局的福利和服务，原因是 他们是退伍军人、退伍军人的家属或幸存者。心血管疾病是导致 退伍军人和平民的重大发病率和死亡率(CDC/国家卫生中心 统计数据)。我一直与退伍军人管理局和非退伍军人管理局资助的临床医生-科学家和基础研究人员联系在一起 在过去的20年里。我也是退伍军人事务部资助的调查员。我作为退伍军人管理局资助的研究的总体重点 科学家将研究炎症、炎性细胞因子和趋化因子以及核因子-κB的致病作用 在心血管疾病中的激活。由于炎症是心血管疾病发病机制中的关键组成部分，而心血管疾病是 退伍军人和平民人口的发病率和死亡率的主要促成因素 性别，我的研究与退伍军人事务部的任务高度相关。此外，高血压、糖尿病、肥胖症和 吸烟使退伍军人和平民都容易患上心血管疾病，我正在进行的研究对进一步的研究是及时和关键的 了解这些慢性病的病理生理学。使用最有前途的研究策略 以及解决问题的方法，我的目标是确定心血管疾病的新治疗靶点。TRAF3相互作用 蛋白2(TRAF3IP2)是一种细胞质适配分子，是至少三个主要的上游调节因子 已知在缺血性心脏病中起病理作用的信号转导通路。 TRAF3IP2激活IKK/NF-κB、JNK/AP-1和p38MAPK，并诱导多种细胞因子的表达 以及具有负性肌力作用的趋化因子。它还调节胶原蛋白的表达和 MMPs。TRAF3IP2是IL-17信号转导的关键中间体，也是参与 缺血性心脏病。我们的初步结果表明，TRAF3IP2也在IL-18信号转导中发挥作用。在……里面 事实上，我们发现TRAF3IP2通过与含有IL-18受体的TIR(Toll/IL-1受体)结构域结合 结合基序似乎不同于负责TRAF3IP2/IL-17R结合的基序。生物信息学 研究表明，TRAF3IP2还可与白介素1受体辅助蛋白(IL-1RACP)、白介素1受体辅助蛋白(IL-1RACP)结合。 1β受体。我们先前报道，TRAF3IP2也在脂多糖/Toll样受体4介导的过程中发挥作用 心肌细胞收缩功能障碍，提示靶向TRAF3IP2可以钝化IL-17、IL-18、IL-1和 内毒素信号，所有这些都在包括心脏缺血性损伤在内的各种心脏病理过程中起着因果作用。 利用体内(遗传和干预)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检查TRAF3IP2、炎症和心力衰竭(HF)之间的关系 体内缺血/非缺血起源及其体外分子机制。我的长期目标是 制定治疗策略以抑制TRAF3IP2的表达。最近，我们通过UTMD瞄准了TRAF3IP2 (超声靶向微泡破坏)介导AS-ODN进入LV，并证明 心脏TRAF3IP2表达显著减少，心肌损伤(梗死面积)，不良重构和 高频发展。此外，我正在进行的研究集中在解开RNA结合的作用 蛋白Larp6(刺激I型和III型胶原表达)和膜锚定蛋白RECK(抑制 多种MMPs、ADAMS、EGFR、uPA和gp130)在不良心脏重构和心力衰竭发生中的作用。 ！！

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. !!