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资助的临床医生和基础研究人员有关 过去25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 科学家将研究炎症，炎症细胞因子和趋化因子和趋化因子和 CVD炎症的抑制剂。由于炎症是CVD发病机理的关键成分，并且 CVD是退伍军人和平民的发病率和死亡率的主要因素 两性的人群，我的研究与VA任务高度相关。由于高血压，糖尿病， 肥胖，吸烟易感退伍军人和平民，无论是CVD，我正在进行的研究都是及时且至关重要的 在进一步了解这些慢性疾病的病理生理学基础的分子机制时。 使用最有前途的研究策略和解决问题的方法，我的目标是确定更新 CVD和相关死亡率钝性进展的治疗靶标和方法。我们确定了两个 表现出承诺的分子：Traf3ip2和Reck。 TRAF3IP2（TRAF3相互作用蛋白2）是细胞质 适配器分子和至少三个主要促炎信号转导的上游调节剂 已知在缺血/非缺血性心脏病中起病理作用的途径。 traf3ip2是 IKK/NF-KB，JNK/AP-1和p38 MAPK的上游调节器，其持续激活使负面激活 心肌肌力作用。它还诱导胶原蛋白和MMP的表达。 traf3ip2也是关键 IL-17，IL-18和TLR4信号中的中间体，所有这些都参与了HF的发展和进展。 RECK（将富含半胱氨酸的蛋白具有Kazal图案诱导的逆转）是膜锚定的MMP调节剂。 它还通过与Adams的物理联系以及IL-6R和GP130发挥抗炎作用。我们的 初步数据表明，缺血/非缺血性的人心力衰竭是 以高水平的traf3ip2和抑制的表达为特征。因此，我的目标和 热情是努力开发TRAF3IP2抑制剂和RECK诱导剂，并调查其 扭转临床前模型中心力衰竭进展的潜力。朝向这个目标，使用分子 建模和对接，我们测试了数千种化合物，并鉴定了两个潜在的小分子 TRAF3IP2抑制剂和一个小分子RECK诱导剂，并向VA提交了发明披露 会员。由于Reck的表达在人类心力衰竭中被下调，因此我正在进行的研究集中在 调查RECK归纳是否钝化压力超载引起的不良心肌重塑和 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，ADAMS和 体内非缺血性起源的炎症和心力衰竭（HF）和其基于其的分子机制 体外表达降低（VA值2022-2026）。我们还在探索是否aav9-ctnt（截断 心脏肌钙蛋白启动子）介导的RECK过表达，特别是在心肌细胞中，将抑制 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于解开 RNA结合蛋白LARP6（刺激胶原I表达）在不良心脏重塑中的作用 和HF开发。