Signaling in T Lymphocyte Development

T 淋巴细胞发育中的信号转导

• 批准号: 7434475
• 负责人: Gerald R. Crabtree
• 金额: $ 32.65万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7434475
• 关键词: Alleles; Apoptotic; Autoantigens; Biochemical; Biochemical Genetics; Biochemical Pathway; CD8B1 gene; Calcineurin; Calcineurin B; Calcium; Cell Death; Cell Nucleus; Cell membrane; Cells; Cessation of life; Chromosome Pairing; Defect; Dendritic Cells; Development; Distant; Endothelial Cells; Epithelial Cells; Family member; Gene Expression; Genes; Genetic screening method; Goals; Hand; Immune; Immunologics; Knockout Mice; Lead; Length; Lymphocyte; Mediating; Mediator of activation protein; Methods; Mitogen-Activated Protein Kinases; Mus; Nuclear Import; Organism; Pathway interactions; Peripheral; Phenotype; Phosphotransferases; Play; Population; Process; Proteins; Recruitment Activity; Research Personnel; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Staging; Stromal Cells; Structure; Synapses; System; T-Cell Development; T-Cell Proliferation; T-Cell Receptor; T-Lymphocyte; Thinking; Thymocyte Selection; Transgenic Mice; Work; analog; base; cell type; digital; gene function; human prostaglandin D2 receptor; molecular assembly/self assembly; pro-apoptotic protein; programs; receptor; response; synaptogenesis; thymocyte; transcription factor

DESCRIPTION (provided by applicant): Perhaps few questions in development have been so intractable as the means by which different cell fates are produced in response to a gradient of signals. These analogue-to-digital switches underlie the determination of cell fates in many organisms. T Lymphocyte development may be one of the best systems to understand this general problem because the critical signals are given at a stage where biochemical, genetic and cell biologic methods can all be brought to play. In lymphocytes, weak or transient signals are thought to produce positive selection (differentiation and proliferation) of T cells capable of reacting to self-MHC on thymic stromal cells. On the other hand, strong signals produced by self-antigen lead to death of cells responding to self-antigen. The pro-apoptotic protein Bim is required for negative selection but is not necessary for positive selection. Conversely, we have recently found that calcineurin is essential in T cells for positive selection, but dispensable for negative selection. Surprisingly calcineurin specifically controls the activation of ERK but not other MAP kinases or IkB, suggesting a revision of the accepted signaling pathways of thymocyte selection. These observations set the stage for a biochemical march from Bim and calcineurin to the molecule(s) that divert signals from positive to negative selection with increasing signal intensity. Current studies support several possible mechanisms by which signals of different intensity could control selection. To avoid the difficulties encountered with forward analysis of biochemical pathways we will work backward from Bim and calcineurin to define the biochemical pathways that control their activity in CD4+, CD8+ thymocytes. Our goal in these studies will be to define the lowest common mediator necessary for activation of both Bim and calcineurin and hence positive and negative selection. We will then determine the mechanism by which this molecule is induced to channel high intensity signals to Bim and low intensity signals to calcineurin. We will also define the processes downstream of calcineurin that mediate positive selection including the mechanism of NFATc nuclear import and export, the set of genes that are dependent on calcineurin activity in positive selection and how these genes give rise to a population of immunologically competent peripheral lymphocytes. Defining these mechanisms should lead to a more complete understanding of immune defense and provide useful information for development of new therapies.

描述（由申请人提供）：也许很少有开发中的问题像响应于信号梯度而产生不同细胞命运的方法那样棘手。这些模拟到数字开关是许多生物体中细胞命运决定的基础。T淋巴细胞发育可能是理解这个普遍问题的最佳系统之一，因为关键信号是在生化、遗传和细胞生物学方法都可以发挥作用的阶段给出的。在淋巴细胞中，弱或瞬时信号被认为产生能够与胸腺基质细胞上的自身MHC反应的T细胞的正选择（分化和增殖）。另一方面，由自身抗原产生的强信号导致响应于自身抗原的细胞死亡。促凋亡蛋白Bim是阴性选择所必需的，但不是阳性选择所必需的。相反，我们最近发现，钙调神经磷酸酶是必不可少的T细胞的积极选择，但否定选择。令人惊讶的是，钙调神经磷酸酶特异性控制ERK的激活，但不控制其他MAP激酶或IkB，这表明胸腺细胞选择的公认信号通路的修订。这些观察结果为从Bim和钙调神经磷酸酶到将信号从正选择转移到负选择的分子（信号强度增加）的生物化学进军奠定了基础。目前的研究支持几种可能的机制，不同强度的信号可以控制选择。为了避免遇到的困难，向前分析的生化途径，我们将工作从Bim和钙调神经磷酸酶向后定义的生化途径，控制其在CD4+，CD8+胸腺细胞的活动。在这些研究中，我们的目标将是确定激活Bim和钙调神经磷酸酶所需的最低共同介质，从而确定积极和消极的选择。然后，我们将确定该分子被诱导以将高强度信号传导至Bim和将低强度信号传导至钙调神经磷酸酶的机制。我们还将定义钙调磷酸酶下游的过程，介导积极的选择，包括NFATc核的进口和出口的机制，一套基因，是依赖于钙调磷酸酶活性的积极选择，以及这些基因如何产生一个群体的免疫能力的外周淋巴细胞。定义这些机制应该会导致对免疫防御的更完整的理解，并为开发新的治疗方法提供有用的信息。