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.

摘要