Signaling Mechanisms of the Drosophila JAK/STAT Pathway

果蝇 JAK/STAT 通路的信号传导机制

• 批准号: 6559614
• 负责人: HONG LUO
• 金额: $ 25.61万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6559614
• 关键词: Drosophilidae; JAK kinase; arthropod genetics; biological signal transduction; cell differentiation; cytokine; enzyme activity; gene deletion mutation; gene expression; gene interaction; genetic regulation; genetic screening; genetic transcription; immunocytochemistry; immunologic substance development /preparation; immunoprecipitation; intermolecular interaction; invertebrate embryology; laboratory mouse; monoclonal antibody; mutant; protein structure function; serial analysis of gene expression; tissue /cell culture; western blottings

DESCRIPTION (provided by applicant): The long-term goal of this study is to understand the molecular and genetic mechanisms of action of the Drosophila JAK/STAT pathway. In mammals, this pathway is critical for hematopoiesis and immune responses, and deregulation of the signaling activity can cause immune disease and leukemia in humans. The fruit fly Drosophila melanogaster has emerged as a genetic paradigm for systematically dissecting the components in this pathway and studying their roles in vivo. Three specific aims are proposed for investigation. In specific aim 1, deletion mutants, and loss of function and gain of function mutations in the Drosophila JAK kinase Hopscotch will be used to test the hypothesis that both positive and negative regulatory domains affect the kinase activity of Hop; activation-specific antibodies will be used to examine where and when this pathway is activated in vivo. In specific aim 2, a genome-wide genetic screen has been conducted, from which several candidate suppressor deficiencies have been isolated. The responsive suppressor genes will be identified using mutant alleles in the deficiency region; the roles of these suppressor genes will be characterized and the mechanism of interaction will be studied. In specific aim 3, target genes of the Hop/Stat92E pathway will be identified using the serial analyses of gene expression (SAGE) technique, and their functional roles studied. These studies should provide important insight into the regulation of the Hop/Stat92E pathway in Drosophila development and may also help to understand oncogenesis caused by hyperactivation of the JAK/STAT pathway in humans.

描述（由申请方提供）：本研究的长期目标是了解果蝇JAK/STAT通路的分子和遗传作用机制。在哺乳动物中，该途径对于造血和免疫反应至关重要，并且信号传导活性的失调可导致人类的免疫疾病和白血病。果蝇Drosophila melanogaster已经成为系统地解剖该通路中的组分并研究其在体内作用的遗传范例。提出了三个具体的调查目标。在具体目标1中，将使用果蝇JAK激酶Hopscotch中的缺失突变体以及功能丧失和功能获得突变来检验阳性和阴性调节结构域均影响Hop的激酶活性的假设;将使用激活特异性抗体来检查该途径在体内何时何地被激活。在具体目标2中，进行了全基因组遗传筛选，从中分离出几种候选抑制基因缺陷。将使用缺陷区域中的突变等位基因鉴定响应性抑制基因;将表征这些抑制基因的作用，并研究相互作用的机制。在具体目标3中，将使用基因表达系列分析（SAGE）技术鉴定Hop/Stat 92 E途径的靶基因，并研究其功能作用。这些研究将为果蝇发育中Hop/Stat 92 E通路的调节提供重要的见解，也可能有助于了解人类JAK/STAT通路过度激活引起的肿瘤发生。