BLRD Research Career Scientist Award Application

摘要 近6300万人（占美国人口的20%）有资格获得VA福利和服务， 他们是退伍军人、家属或退伍军人的遗属。心血管疾病（CVD）导致 退伍军人和平民的显著发病率和死亡率（CDC/国家卫生中心 统计）。我一直与VA和非VA资助的临床科学家和基础研究人员， 过去的25年我也是一名退伍军人事务部资助的调查员。作为退伍军人管理局资助的研究项目， 科学家是调查炎症，炎症细胞因子和趋化因子的因果作用， CVD炎症抑制剂。由于炎症是CVD发病机制的关键组成部分， CVD是退伍军人和平民发病率和死亡率的主要因素 我的研究与退伍军人事务部的使命高度相关。因为高血压，糖尿病， 肥胖和吸烟使退伍军人和平民容易患心血管疾病，我正在进行的研究是及时和关键的 进一步了解这些慢性疾病病理生理学的分子机制。 使用最有前途的研究策略和解决问题的方法，我的目标是找出更新的 治疗目标和方法，以减缓CVD的进展和相关的死亡率。我们确定了两 有希望分子：TRAF 3 IP 2和RECK。TRAF 3 IP 2（TRAF 3 Interacting Protein 2）是一种细胞质内的蛋白质。 衔接分子和至少三种主要促炎信号转导的上游调节因子 已知在缺血性/非缺血性心脏病中起病理作用的途径。TRAF 3 IP 2是 IKK/NF-κ B、JNK/AP-1和p38 MAPK的上游调节因子，其持续激活产生负性作用， 心肌变力作用。它还诱导胶原和MMPs的表达。TRAF 3 IP 2也是一个关键的 IL-17、IL-18和TLR 4信号传导的中间体，所有这些都参与HF的发展和进展。 RECK（Reversion Inducing Cysteine Rich Protein with Kazal Motifs）是一种膜锚定MMP调节剂。 它还通过与亚当斯、IL-6 R和gp 130的物理结合发挥抗炎作用。我们 初步数据显示，缺血/非缺血性起源的人心力衰竭（缺血性心脏）， 其特征在于高水平的TRAF 3 IP 2和抑制的RECK表达。因此，我的目标和 我们的热情是致力于开发TRAF 3 IP 2抑制剂和RECK诱导剂，并研究其 在临床前模型中减缓心力衰竭进展的潜力。为了实现这一目标，使用分子 通过建模和对接，我们测试了数千种化合物，并确定了两种潜在的小分子 TRAF 3 IP 2抑制剂和一种小分子RECK诱导剂，并向VA和 附属机构。由于RECK表达在人类心力衰竭中下调，我正在进行的研究集中在 研究RECK诱导是否减弱压力超负荷诱导的不良心肌重塑， 临床前模型中的心力衰竭。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，我将确定RECK，MMPs，亚当斯， 炎症和非缺血性心脏衰竭（HF）的体内及其分子机制 体外表达降低（VA Merit 2022-2026）。我们还在探索AAV 9-cTnT（截短的 心肌肌钙蛋白启动子）介导的RECK过表达，特别是在心肌细胞中，将抑制 在临床前模型中心力衰竭的进展。此外，我正在进行的研究集中在解开 RNA结合蛋白Larp 6（刺激胶原I表达）在不利的心脏重塑中的作用 HF的发展。

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 25 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 inhibitors of inflammation 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. Since hypertension, diabetes, obesity, and smoking predispose veterans and civilians alike to CVD, my ongoing studies are timely and critical in further understanding the molecular mechanisms underlying the pathophysiology of these chronic diseases. Using the most promising research strategies and problem-solving approaches, my goals are to identify newer therapeutic targets and approaches to blunt progression of CVD and associated mortality. We identified two molecule that show promise: TRAF3IP2 and RECK. TRAF3IP2 (TRAF3 Interacting Protein 2) is a cytoplasmic adapter molecule and an upstream regulator of at least three major proinflammatory signal transduction pathways that are known to play a pathological role in ischemic/non-ischemic cardiac diseases. TRAF3IP2 is an upstream regulator of IKK/NF-kB, JNK/AP-1 and p38 MAPK, whose persistent activation exerts negative myocardial inotropic effects. It also induces the expression of collagens and MMPs. TRAF3IP2 is also a critical intermediate in IL-17, IL-18 and TLR4 signaling, all of which are involved in HF development and progression. RECK (Reversion Inducing Cysteine Rich Protein with Kazal Motifs) is a membrane anchored MMP regulator. It also exerts anti-inflammatory effects by physically associating with ADAMs, and IL-6R and gp130. Our preliminary data show that human heart failure of ischemic/non-ischemic origin (explanted hearts) is characterized by high levels of TRAF3IP2 and suppressed expression of RECK. Therefore, my goal and passion are to work towards developing TRAF3IP2 inhibitors and RECK inducers and investigate their potential in blunting the progression of heart failure in preclinical models. Towards this goal, using molecular modeling and docking, we tested several thousands of compounds, and identified two potential small molecule TRAF3IP2 inhibitors and one small molecule RECK inducer, and submitted invention disclosures to VA and the affiliate. Since RECK expression is downregulated in human heart failure, my ongoing studies are focused on investigating whether RECK induction blunts pressure overload-induced adverse myocardial remodeling and heart failure in preclinical models. Utilizing both in vivo (genetic and interventional) and in vitro (cardiomyocytes and cardiac fibroblasts) models, I will determine the relationship between RECK, MMPs, ADAMs, and inflammation and heart failure (HF) of non-ischemic origin in vivo and the molecular mechanisms underlying its reduced expression in vitro (VA Merit 2022-2026). We are also exploring whether AAV9-cTnT (truncated cardiac troponin promoter)-mediated RECK overexpression, specifically in cardiomyocytes, will inhibit the progression of heart failure in a preclinical model. In addition, my ongoing studies are focused on unraveling the roles of the RNA binding protein Larp6 (stimulates collagen I expression) in adverse cardiac remodeling and HF development.