Inflammatory cytokine-mediated induction of HIV cardiomyopathy

炎症细胞因子介导的 HIV 心肌病诱导

基本信息

批准号：
7284561
负责人：
Jennifer Yearley
金额：
$ 12.31万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-06 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7284561
关键词：
Acquired Immunodeficiency Syndrome Address Adverse effects Agonist Anatomy Animal Model Animals Cardiac Cardiomyopathies Cardiovascular Diseases Cell Line Cells Chronic Class Clinical Congenital Heart Defects Congestive Heart Failure Data Development Dilatation - action Dilated Cardiomyopathy Environment Environmental Risk Factor Evaluation Functional disorder General Population HIV Heart Heart Diseases Heart failure Heating Human In Vitro Individual Infection Inflammation Inflammatory Inflammatory Response Pathway Interleukin-18 Investigation Laboratories Lead Lesion Ligand Binding Ligation Long-Term Effects Macaca mulatta Mediating Mental Depression Messenger RNA Mitogen-Activated Protein Kinases Modeling Mycobacterium avium Myocardial Myocardial tissue Myocardium Pathogenesis Pathological Dilatation Pathology Pathway interactions Population Production Proteins Rate Recurrence Relative (related person)Research Research Personnel Research Training Resources Role SIV Secondary to Signal Transduction Signal Transduction Pathway Stimulus Toll-Like Receptor 2 Training Universities Up-Regulation Ventricular Ventricular Dysfunction Ventricular Function Veterinary Medicine Veterinary Schools Viral Virus Diseases Washington Work base career college cytokine environmental agent experience in vivo insight macrophage monocyte peripheral blood prevent response

项目摘要

DESCRIPTION (provided by candidate): Dr. Jennifer Yearley graduated with her DVM degree from Washington State University College of Veterinary Medicine in 2001, and completed training in veterinary anatomic pathology at the NEPRC in July of 2006. She was involved with studies of bacterial pathogenesis while in veterinary school, and has been working in animal models of lentiviral pathogenesis and AIDS since 2002. Dr. Yearley's research at the NEPRC has centered on the pathogenesis of cardiomyopathy in the context of SIV/HIV infection, and this work forms the basis of her present doctoral studies. Dr. Yearley ultimately intends an academic research career examining the role of inflammation in cardiovascular disease. Cardiomyopathy occurs at much higher rates among HIV-infected people than in the general population and preliminary studies conducted at the NEPRC using the SIV-model of HIV infection, have implicated exaggerated Myocardial inflammatory cytokine responsiveness to stimulation with ubiquitous agents known to engage toll-like receptor 2 (TLR2) as important contributory factors to development of cardiac dysfunction. Based on these findings, we hypothesize that HIV-infected individuals show increased TLR2 expression and/or amplified TLR2-mediated signal transduction on myocardial cell populations, with resulting enhancement of cardiac inflammatory cytokine responses and subsequent ventricular dysfunction, pathological structural remodeling, and ultimately heart failure. To address the predictions made by this hypothesis, in our first aim we will subject SIV-infected rhesus monkeys to long-term, systemic stimulation with heat-inactivated Mycobacterium avium, assessing myocardial TNFalpha, IL-1beta, and IL-18 mRNA and protein levels, and correlating systemic and myocardial cytokine levels with the development and progression of cardiac dysfunction and remodeling. In our second aim, we will characterize the relationship between levels of TLR2 expression and systemic and myocardial inflammatory cytokine production in response to TLR2 stimulation in the context of SIV infection. In our third aim, we will characterize differences in inflammatory signal transduction pathway activation in SIV/HIV infection in response to TLR2 ligation. The NEPRC is an outstanding environment for research training, with superb facilities, unique resources, and world-class researchers, providing a rigorous context for pursuit of scientific investigation.

描述（由候选人提供）：Jennifer Yearley博士于2001年从华盛顿州立大学兽医学院获得DVM学位，并于2006年7月在NEPRC完成了兽医解剖病理学培训。关于在SIV/HIV感染的背景下心肌病的发病机理，这项工作构成了她目前的博士研究的基础。 Yearley博士最终打算一项学术研究职业，检查炎症在心血管疾病中的作用。与一般人群相比，使用HIV感染的SIV模型在NEPRC进行的一般人群中，心肌病的发生率要高得多，这意味着夸张的夸张的心肌炎症细胞因子对刺激对刺激对无处不在的受体2（TOLL-LIKE受体2（TLR）的刺激刺激的反应（TLR 2（TLR））的发展是重要的。基于这些发现，我们假设感染HIV的个体在心肌细胞群体上表现出增加的TLR2表达和/或扩增的TLR2介导的信号转导，导致心脏炎症细胞因子反应增强，并随后的心室功能障碍，病理结构结构重塑，并最终的心脏失败。为了解决这一假设的预测，在我们的第一个目标中，我们将通过热灭活的雄性分枝杆菌进行长期，全身性刺激，评估心肌tnfalpha，IL-1Beta，IL-1Beta，IL-18和IL-18和蛋白质和蛋白质水平，以及与系统的cy级和肌动蛋白水平的发展，并评估心肌tnfalpha，IL-1Beta，IL-1Beta，IL-1Beta和Il-18重塑。在我们的第二个目标中，我们将表征TLR2表达水平与系统性和心肌炎症细胞因子在SIV感染中响应TLR2刺激的关系。在我们的第三个目标中，我们将表征响应TLR2连接的SIV/HIV感染中炎症信号转导途径激活的差异。 NEPRC是研究培训的杰出环境，拥有出色的设施，独特的资源和世界一流的研究人员，为追求科学研究提供了严格的背景。