The Regulation of T Cell Development

T 细胞发育的调控

基本信息

批准号：
7382574
负责人：
STEPHEN M HEDRICK
金额：
$ 45.63万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
1984
资助国家：
美国
起止时间：
1984-07-01 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7382574
关键词：
4-Hydroxy-Tamoxifen Ablation Address Affect Alleles Autoimmunity Bone Marrow Cataloging Catalogs Cell Differentiation process Cells Characteristics Codon Nucleotides Condition Congenital Abnormality Defect Development Disease Equilibrium Extracellular Signal Regulated Kinases Family Fetal Thymic Organ Culture Fluorescence Gatekeeping Genetic Recombination Genetic Transcription Glycine Goals Hematopoietic stem cells Hyperactive behavior Immunologic Deficiency Syndromes In Vitro Knock-in Mouse Knowledge Label Life Lymphocyte Mass Spectrum Analysis Measures Mediating Mitogen-Activated Protein Kinases Modeling Mouse Strains Mus Mutant Strains Mice Mutation N(6)-ribosyladenine Pathway interactions Phosphorylation Point Mutation Population Process Protein Kinase Proteins Regulation Reporter Reporting Research Personnel Resolution Role Signal Pathway Signal Transduction Site System T-Cell Development T-Lymphocyte Testing Thymocyte Selection Time Transfection Transgenic Mice analog base concept extracellular in vivo inhibitor/antagonist kinase inhibitor mutant novel progenitor receptor research study small hairpin RNA thymocyte tool transcription factor

项目摘要

DESCRIPTION (provided by applicant): The multi-step development and selection of T cell progenitors produces a mature population finely tuned to the recognition of self-encoded MHC alleles. Congenital defects in this process can result in a variety of diseases spanning immunodeficiency states to hyperactivity and autoimmunity. We propose to expand knowledge of the selection steps in T cell development, by focusing on a critical component of receptor- mediated signaling, the extracellular signal-regulated kinase (Erk) pathway. Three different mouse mutants have been produced that enable us to: visualize activation of the pathway, selectively inhibit the pathway, or identify new downstream substrates involved in the process of T cell differentiation. In mice with GFP expressed under control of the Id3 locus, lymphocytes fluoresce upon activation of Erk and its alteration of transcription factors of the Ets family. In mice with a conditional Erk deficiency we can cause deletion of the locus by treatment with 4-hydroxytamoxifen. And, in mice with a site-directed point mutation in Erk2, we can utilize synthetic ATP analogs to directly label natural substrates. We will use these strains of mice to dissect the timing and strength of extracellular signals and how this information guides the process of selection and commitment. Our long-term goal is to exploit these tools to characterize novel pathways of cellular differentiation downstream of Erk.

描述（由申请人提供）：T细胞祖细胞的多步开发和选择会产生一个成熟的人群，以识别自我编码的MHC等位基因。在此过程中，先天性缺陷会导致各种疾病，这些疾病跨越了免疫缺陷状态，以使其多动症和自身免疫性。我们建议通过关注受体介导的信号传导的关键成分，即细胞外信号调节激酶（ERK）途径，以扩展对T细胞发育中的选择步骤的知识。已经产生了三种不同的小鼠突变体，使我们能够：可视化途径的激活，选择性地抑制途径或识别参与T细胞分化过程的新的下游底物。在以ID3基因座的控制下表达的GFP的小鼠中，ERK激活后淋巴细胞荧光及其对ETS家族转录因子的改变。在有条件的ERK缺乏症的小鼠中，我们可以通过4-羟基莫昔芬治疗来删除基因座。并且，在ERK2中具有位置定向点突变的小鼠中，我们可以利用合成ATP类似物直接标记天然底物。我们将使用这些小鼠菌株来剖析细胞外信号的时间和强度，以及该信息如何指导选择和承诺的过程。我们的长期目标是利用这些工具来表征ERK下游细胞分化的新途径。