BLRD Research Career Scientist Award Application

BLRD 研究职业科学家奖申请

• 批准号: 10587293
• 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 2029-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10587293
• 关键词: Affect; Aldosterone; Angiotensin II; Antiinflammatory Effect; Atherosclerosis; Award; Binding; Biopsy; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cell Death; Characteristics; Chronic Disease; Collaborations; Collagen; Colorado; Complement Factor H; Critical Pathways; Cytoplasm; Data; Deposition; Development; Diabetes Mellitus; Disclosure; Disease Progression; Docking; Eligibility Determination; Endothelial Cells; Etiology; Family member; Fibrillar Collagen; Fibroblasts; Florida; Functional disorder; Funding; GPI Membrane Anchors; Gene Deletion; Genes; Genetic; Goals; Healthcare; Healthcare Systems; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Human; Hypertension; Hypertrophy; IL17 gene; IL18 gene; IL6ST gene; In Vitro; Inflammation; Inflammatory; Injury; Interleukin-1; Interleukin-6; Interleukins; Intervention; Intervention Studies; Ischemia; Isoproterenol; Knock-in Mouse; Knock-out; MAP Kinase Gene; MAPK8 gene; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Mediating; Mediator; Membrane; Messenger RNA; Microbubbles; Mission; Modeling; Molecular; Morbidity - disease rate; Mutate; Myocardial; Myocardial Ischemia; Myocardial dysfunction; NF-kappa B; Nodal; Obesity; Oxidative Stress; Pathogenesis; Pathologic; Patient-Focused Outcomes; Patients; Persons; Phase; Pilot Projects; Play; Population; Pre-Clinical Model; Problem Solving; Progressive Disease; Proliferating; Proteins; Publications; RNA; RNA-Binding Proteins; Recombinant Interleukins; Reperfusion Therapy; Reporting; Research; Research Personnel; Ribonucleoproteins; Role; Scientist; Services; Signal Transduction; Signal Transduction Pathway; Smoking; Survivors; TLR4 gene; TNF receptor-associated factor 3; Testing; Therapeutic; Tissues; Transcription Factor AP-1; Transgenic Mice; Troponin; United States National Center for Health Statistics; Universities; Ventricular Remodeling; Veterans; Work; antagonist; aortic valve replacement; career; cell type; chemokine; comorbidity; coronary fibrosis; cysteine rich protein; cytokine; efficacy testing; functional improvement; gain of function; improved; in vivo; inhibitor; invention; ischemic injury; loss of function; migration; military veteran; molecular modeling; mortality; mouse model; myocardial injury; neutralizing antibody; new therapeutic target; overexpression; p38 Mitogen Activated Protein Kinase; pharmacologic; posttranscriptional; pressure; promoter; sex; small molecule; small molecule inhibitor; stem; therapeutic target; tissue injury; transcription factor; ubiquitin ligase; ultrasound

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.

抽象的 近 6300 万人（占美国人口的 20%）有资格享受 VA 福利和服务，因为 他们是退伍军人、退伍军人的家属或幸存者。心血管疾病 (CVD) 会导致 退伍军人和平民的显着发病率和死亡率（疾病预防控制中心/国家卫生中心 统计数据）。我曾与 VA 和非 VA 资助的临床医生科学家和基础研究人员合作 过去25年。我也是 VA 资助的调查员。作为 VA 资助的我的研究总体重点 科学家的任务是研究炎症、炎症细胞因子和趋化因子的因果作用，以及 CVD 中的炎症抑制剂。由于炎症是 CVD 发病机制的关键组成部分，并且 CVD 是退伍军人和平民发病率和死亡率的主要影响因素 对于男女群体，我的研究与退伍军人事务部的使命高度相关。由于高血压、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且关键的 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 减缓CVD进展和相关死亡率的治疗目标和方法。我们确定了两个 显示出前景的分子：TRAF3IP2 和 RECK。 TRAF3IP2（TRAF3 相互作用蛋白 2）是一种细胞质 接头分子和至少三个主要促炎信号转导的上游调节因子 已知在缺血性/非缺血性心脏病中发挥病理作用的途径。 TRAF3IP2 是 IKK/NF-kB、JNK/AP-1 和 p38 MAPK 的上游调节因子，其持续激活会产生负面影响 心肌正性肌力作用。它还诱导胶原蛋白和基质金属蛋白酶的表达。 TRAF3IP2 也是一个关键 IL-17、IL-18 和 TLR4 信号传导的中间体，所有这些信号都参与心力衰竭的发生和进展。 RECK（具有 Kazal 基序的逆转诱导富含半胱氨酸蛋白）是一种膜锚定的 MMP 调节剂。 它还通过与 ADAM、IL-6R 和 gp130 物理结合来发挥抗炎作用。我们的 初步数据表明，人类缺血性/非缺血性心力衰竭（移植心脏）是 其特征是高水平的 TRAF3IP2 和抑制的 RECK 表达。因此，我的目标和 我们热衷于开发 TRAF3IP2 抑制剂和 RECK 诱导剂并研究它们的 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，利用分子 建模和对接，我们测试了数千种化合物，并鉴定了两种潜在的小分子 TRAF3IP2 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，我正在进行的研究重点是 研究 RECK 诱导是否会减弱压力超负荷引起的不良心肌重塑以及 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、MMP、ADAM 和 体内非缺血性起源的炎症和心力衰竭（HF）及其背后的分子机制 体外表达减少（VA Merit 2022-2026）。我们也在探索AAV9-cTnT（截短的 心肌肌钙蛋白启动子）介导的 RECK 过度表达，特别是在心肌细胞中，将抑制 临床前模型中心力衰竭的进展。此外，我正在进行的研究重点是解开 RNA 结合蛋白 Larp6（刺激 I 型胶原表达）在不良心脏重塑中的作用 和高频发展。