Molecular Mechanisms of Th1/Th2 Development

Th1/Th2 发育的分子机制

• 批准号: 7218052
• 负责人: Ralph C Budd
• 金额: $ 151.55万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7218052
• 关键词: Autoimmune Diseases; CASP8 and FADD-like apoptosis regulating protein; CD4 Positive T Lymphocytes; Cessation of life; Cytokine Gene; Development; Environment; Equilibrium; Experimental Autoimmune Encephalomyelitis; Funding; GTP-Binding Proteins; Gene Expression Regulation; Grant; Histamine; Hour; Immune; Immunogenetics; Immunology; Institutes; Institution; Interleukin-4; Interleukin-6; Memory; Molecular; NF-kappa B; NFAT Pathway; Pathway interactions; Pattern; Production; Program Research Project Grants; Publications; Regulation; Research Personnel; Signal Pathway; Signal Transduction; Susceptibility Gene; T-Lymphocyte; Th2 Cells; Universities; Vermont; Viral; cell type; cytokine; in vivo Model; inhibitor/antagonist; killings; memory CD4 T lymphocyte; programs; receptor; transcription factor

DESCRIPTION (provided by applicant): This is the first renewal application for this Program Project Grant, currently at 3.5 years of a 4 year grant. The focus has been and remains a study of the molecular and cellular pathways that regulate the balance of Th1 and Th2 cytokine patterns. It makes a particular effort to integrate specific signal pathways with important cellular questions. These studies make use of several in vivo models of infectious and autoimmune diseases as well as immune memory. It also examines an aspect of Th1/Th2 regulation that is less frequently considered, the cellular interactions that influence the Th1/Th2 balance once it is established; in this case by gamma/delta T cells. This Program Project also combines the expertise of two institutions, The University of Vermont (UVM) and the Trudeau Institute, two hours from UVM in Saranac Lake, NY. The UVM investigators (Drs. Ralph Budd, Mercedes Rincon, Sally Huber, Cory Teuscher) have expertise is cell signaling, immunogenetics, and viral immunology, whereas the Trudeau investigators (Drs. Susan Swain, Laura Haynes, and Markus Mohrs) have expertise in the study of immune memory and cytokine gene regulation, both of which are critical to our studies. The principal signal pathways studied in this Program Project converge on two important transcription factors for cytokine gene regulation, NFAT and NF-kB. IL-6 triggers IL-4 production in naive CD4+ -T cells via NFATc2 (Project 1), whereas gamma/delta T cells express high levels of FasL via NFAT which selectively kill Th2 cells in a Fas-dependent manner (Project 3). Similarly, c-FLIP (the death receptor inhibitor studied in Project 2) and the Histamine 1 Receptor (H1R, a susceptibility gene locus for EAE studied in Project 4) converge on the NF-kB pathway, c-FLIP signals NF-kappaB via RIP to costimulate T cells, and H1R connects to G-proteins and PKC theta to signal NF-kappaB. All four projects examine how these signal pathways and cell types influence the Th1/Th2 environment. In addition, Projects 1 and 2 also examine how the c-FLIP/NF-kappaB and IL-6/NFAT pathways influence the transition from effector Th1/Th2 to memory CD4+ T cell. Progress during the current funding period has been substantial (over 30 publications), 8 of which are multi-authored among the Program investigators, the renewal application includes two new investigators, Dr. Cory Teuscher, a leading immunogeneticist, and Dr. Markus Mohrs, with expertise in cytokine gene regulation.

描述(由申请人提供)： 这是该计划项目赠款的第一次续签申请，目前是4年期赠款中的3.5年。重点一直是并仍然是对调节Th1和Th2细胞因子模式平衡的分子和细胞通路的研究。它特别努力地将特定的信号通路与重要的细胞问题结合起来。这些研究利用了几种感染性和自身免疫性疾病的体内模型以及免疫记忆。它还研究了Th1/Th2调节的一个较少被考虑的方面，即一旦Th1/Th2平衡建立，影响Th1/Th2平衡的细胞相互作用；在这种情况下，通过伽马/增量T细胞。该项目还结合了两个机构的专业知识，佛蒙特州大学(UVM)和特鲁多研究所，距离纽约州萨拉纳克湖的UVM有两个小时的车程。UVM研究员(Ralph Budd博士、Mercedes Rincon博士、Sally Huber博士、Cory Teuscher博士)拥有细胞信号、免疫遗传学和病毒免疫学方面的专业知识，而Trudeau研究员(Susan Swain博士、Laura Haynes博士和Markus Mohars博士)拥有免疫记忆和细胞因子基因调控研究方面的专业知识，这两项研究对我们的研究至关重要。 本项目中研究的主要信号通路集中在两个重要的转录因子上，即NFAT和NF-kB。IL-6通过NFATc2(项目1)在初始的CD4+-T细胞中触发IL-4的产生，而伽马/Delta T细胞通过NFAT表达高水平的FasL，以Fas依赖的方式选择性地杀伤Th2细胞(项目3)。同样，c-FLIP(项目2中研究的死亡受体抑制剂)和组胺1受体(H1R，项目4中研究的EAE易感基因位点)在NF-kB途径上收敛，c-FLIP通过RIP信号转导NF-kappaB以共刺激T细胞，H1R连接G蛋白和PKC theta以信号转导NF-kappaB。所有四个项目都研究了这些信号通路和细胞类型如何影响Th1/Th2环境。此外，项目1和2还研究了c-flip/NF-kappaB和IL-6/NFAT通路如何影响从效应器Th1/Th2到记忆性CD4+T细胞的转变。 在当前的资助期间取得了很大的进展(超过30篇论文)，其中8篇是项目研究人员的多作者，续签申请包括两名新的研究人员，领先的免疫遗传学家Cory Teuscher博士和具有细胞因子基因调控专业知识的Markus Mohars博士。