Apoptotic Signaling in Viral Myocarditis

病毒性心肌炎中的细胞凋亡信号传导

• 批准号: 6521563
• 负责人: Roberta Lynn DeBiasi
• 金额: $ 11.45万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6521563
• 关键词: Reoviridae; apoptosis; biological signal transduction; cardiac myocytes; cysteine endopeptidases; flow cytometry; functional /structural genomics; gel electrophoresis; gene expression; histopathology; immunocytochemistry; laboratory mouse; mass spectrometry; microarray technology; mitogen activated protein kinase; molecular pathology; myocarditis; myocardium; oligonucleotides; proteomics; terminal nick end labeling; virus cytopathogenic effect; virus diseases

DESCRIPTION (provided by applicant): This proposal describes a 5-year training program for the development of an independent academic career in Laboratory Medicine and Infectious Diseases. The program will promote the command of genomic and proteomic approaches applied to the study of viral pathogenesis. Kenneth L. Tyler will mentor the P.I.'s scientific development. Dr. Tyler is a recognized leader in the field of viral pathogenesis. As Professor of Neurology, Microbiology, Immunology, and Medicine, he has trained numerous postdoctoral fellows and graduate students. To enhance the training, the program will enlist the expertise of a multidisciplinary board of senior scientists, who will provide scientific and career advice. The University of Colorado provides an ideal setting for training physician-scientists by integrating expertise from diverse resources into customized programs. This environment maximizes the potential for the PI to establish a scientific niche from which a successful academic career can be constructed. Research will focus on delineating and targeting apoptotic signaling pathways in viral myocarditis. Dr.Tyler's laboratory has used reoviruses to study viral and cellular mechanisms of apoptotic cell death, both in vitro and in well-characterized murine models of viral encephalitis and myocarditis. Specific aims of this project are (1) to identify the importance of apoptosis as a critical determinant of virus-induced myocarditis, (2) to characterize virus-induced myocarditic signaling pathways in vitro and vivo at the transcriptional and translational levels, and (3) to target critical identified pathways in vivo, as a novel therapeutic strategy for viral myocarditis. Proposed experiments involve detailed analysis of infected murine cardiac myocytes and tissues, using myocarditic and non-myocarditic viruses. Virologic, histologic, immunohistochemical, genomic and proteomic approaches will be employed. Identified pathways will be targeted using specific inhibitors and mice with genetic mutations in pertinent signaling pathways. These studies are designed to identify specific cellular mechanisms of virus-induced apoptosis in the pathogenesis of viral myocarditis. Identification of these pathways is critical for the development of novel therapies for viral myocarditis and other diseases involving apoptotic tissue damage.

描述（由申请人提供）：该提案描述了一个为期 5 年的培训计划，旨在发展检验医学和传染病方面的独立学术职业。该计划将促进对应用于病毒发病机制研究的基因组和蛋白质组学方法的掌握。 肯尼思·泰勒 (Kenneth L. Tyler) 将指导 P.I. 的科学发展。泰勒博士是病毒发病机制领域公认的领导者。 作为神经病学、微生物学、免疫学和医学教授，他培养了众多博士后和研究生。 为了加强培训，该计划将招募由资深科学家组成的多学科委员会的专业知识，他们将提供科学和职业建议。 科罗拉多大学通过将不同资源的专业知识整合到定制项目中，为培训医师科学家提供了理想的环境。 这种环境最大限度地发挥了 PI 建立科学利基的潜力，从而构建成功的学术生涯。 研究将集中于描绘和靶向病毒性心肌炎中的细胞凋亡信号通路。 泰勒博士的实验室使用呼肠孤病毒在体外以及在病毒性脑炎和心肌炎的良好表征的小鼠模型中研究细胞凋亡的病毒和细胞机制。 该项目的具体目标是（1）确定细胞凋亡作为病毒诱导的心肌炎的关键决定因素的重要性，（2）在转录和翻译水平上表征体外和体内病毒诱导的心肌炎信号通路，以及（3 ）针对体内已确定的关键途径，作为病毒性心肌炎的新型治疗策略。 拟议的实验涉及使用心肌病和非心肌病病毒对受感染的小鼠心肌细胞和组织进行详细分析。将采用病毒学、组织学、免疫组织化学、基因组学和蛋白质组学方法。将使用特定的抑制剂和相关信号通路中具有基因突变的小鼠来靶向已确定的通路。 这些研究旨在确定病毒性心肌炎发病机制中病毒诱导细胞凋亡的特定细胞机制。 识别这些途径对于开发病毒性心肌炎和其他涉及细胞凋亡组织损伤的疾病的新疗法至关重要。