CD45 REGULATION OF T CELL TYROSINE KINASES

T 细胞酪氨酸激酶的 CD45 调节

基本信息

  • 批准号:
    6149797
  • 负责人:
  • 金额:
    $ 11.34万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    1996
  • 资助国家:
    美国
  • 起止时间:
    1996-02-15 至 2002-01-31
  • 项目状态:
    已结题

项目摘要

Recognition of antigen by the T cell antigen receptor complex (TCR) leads to the activation of protein tyrosine kinases (PTKs), the generation of second messengers from the hydrolysis of phosphatidylinositol (PI), and ultimately an appropriate T cell immune response. Recent studies have demonstrated that the transmembrane tyrosine phosphatase (PTP) CD45 is essential for T cell activation. In CD45-negative (CD45-) mutants of various T cell lines, the TCR is uncoupled from PI hydrolysis and PTK activation. In these CD45- T cells, the kinase activity of the src family PTKs lck and fyn is altered, implying that one critical aspect of the role of CD45 in T cell activation is the modulation of lck and fyn activity. Our central hypothesis is that CD45 regulates the activity of lck, fyn, and a third PTK, ZAP-70, and that this regulation is purposefully altered during T cell activation to allow signal transduction to occur. We propose a model in which CD45 normally maintains lck, fyn, and ZAP-70 in a relatively inactive state through the control of phosphorylation of critical regulatory tyrosine residues. The goal of the proposed studies is to explore the validity of this model and, in so doing, elucidate the precise molecular nature of the regulation of lck, fyn, and ZAP-70 by CD45. First, the effect of T cell activation on the catalytic activity and specific phosphorylation of lck, fyn, and ZAP-70 will be characterized using in vitro kinase assays and highly specific phosphopeptide mapping. These studies will be done in normal murine splenic T cells and a variety of T cell lines and clones to allow the selection of a model system that most closely approximates the normal T cell. We will then compare the identified changes in activity and phosphorylation of lck, fyn, and ZAP-70 seen after activation to those seen in situations where CD45 activity is known to be diminished, namely pharmacologic inhibition of CD45 and cD45 mutant T cell lines or clones. The focus will then shift to the effects of TCR-mediated activation on CD45 itself, in terms of its phosphatase activity and phosphorylation. A temporal correlation between the post- activation changes in CD45 and those in lck, fyn, and ZAP-70 can then be evaluated. In this regard, we present new data in this proposal that CD45 activity is decreased after activation through the TCR. Finally, we will determine the effects of the identified CD45-regulated phosphorylations of lck on lck enzymatic activity and the ability of lck to transduce an activation signal after TCR engagement, using a site-directed mutagenesis and transfection approach in an lck-deficient T cell line. Unraveling the molecular mechanisms of the interaction between CD45 and these critical T cell PTKs will aid our understanding of how an immune response is generated and maintained. Furthermore, our results may suggest specific strategies to interrupt aberrant immune responses at a very proximal site, potentially through specific targeting of these PTKs or CD45 itself.
T细胞抗原受体复合体(TCR)对抗原的识别作用 对蛋白酪氨酸激酶(PTKs)的激活,产生 来自磷脂酰肌醇(PI)水解的第二信使,以及 最终会产生适当的T细胞免疫反应。最近的研究表明 证明了跨膜酪氨酸磷酸酶(PTP)CD45是 对T细胞的激活至关重要。在CD45阴性(CD45-)突变体中 不同的T细胞系,TCR是PI水解酶和PTK解偶联的 激活。在这些CD45-T细胞中,src家族的激酶活性 更改了PTK lck和fyn,这意味着角色的一个关键方面 CD45在T细胞活化中的作用是对LCK和FYN活性的调节。 我们的中心假设是CD45调节LCK,FYN, 和第三种PTK,ZAP-70,这种调节被故意改变 在T细胞激活期间,以允许信号转导发生。我们建议 CD45通常将LCK、FYN和ZAP-70保持在 通过控制蛋白的磷酸化达到相对不活跃的状态 关键的调节酪氨酸残基。拟议研究的目标是 为了探索这个模型的有效性,并在这样做的同时,阐明 LCK、FYN和ZAP-70调控的精确分子本质 CD45。首先,T细胞活化对催化活性的影响和 我们将研究lck、fyn和zap-70的特异性磷酸化。 使用体外激酶分析和高度特异的磷酸多肽定位。 这些研究将在正常小鼠脾T细胞和各种 T细胞系和克隆体,以允许选择 最接近正常T细胞。然后我们将比较 确认Lck、Fyn和ZAP-70的活性和磷酸化的变化 在激活后看到的与在CD45活动为 已知的减弱,即CD45和CD45的药物抑制 突变的T细胞系或克隆。然后,重点将转移到 TCR介导的CD45自身的磷酸酶活化 活性和磷酸化。后两者之间的时间相关性- 然后,CD45以及LCK、FYN和ZAP-70中的激活变化可以 已评估。在这方面,我们在这项提案中提出了新数据,即CD45 通过TCR激活后,活性降低。最后,我们会 确定已识别的CD45调节的磷酸化的影响 Lck对Lck酶活性及转导An能力的影响 TCR结合后的激活信号,使用定点突变 以及在Lck缺陷的T细胞系中的转染方法。解开 CD45与这些临界T细胞相互作用的分子机制 细胞PTK将有助于我们了解免疫反应是如何进行的 生成并维护。此外,我们的结果可能会提出具体的 阻断近端异常免疫反应的策略, 可能通过特定靶向这些PTK或CD45本身。

项目成果

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CHRISTOPHER M BURNS其他文献

CHRISTOPHER M BURNS的其他文献

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{{ truncateString('CHRISTOPHER M BURNS', 18)}}的其他基金

Safe and effective anti CD154 antibodies for therapeutic intervention
用于治疗干预的安全有效的抗 CD154 抗体
  • 批准号:
    8609546
  • 财政年份:
    2012
  • 资助金额:
    $ 11.34万
  • 项目类别:
CD45 REGULATION OF T CELL TYROSINE KINASES
T 细胞酪氨酸激酶的 CD45 调节
  • 批准号:
    2653855
  • 财政年份:
    1996
  • 资助金额:
    $ 11.34万
  • 项目类别:
CD45 REGULATION OF T CELL TYROSINE KINASES
T 细胞酪氨酸激酶的 CD45 调节
  • 批准号:
    2330425
  • 财政年份:
    1996
  • 资助金额:
    $ 11.34万
  • 项目类别:
CD45 REGULATION OF T CELL TYROSINE KINASES
T 细胞酪氨酸激酶的 CD45 调节
  • 批准号:
    2871523
  • 财政年份:
    1996
  • 资助金额:
    $ 11.34万
  • 项目类别:
CD45 REGULATION OF T CELL TYROSINE KINASES
T 细胞酪氨酸激酶的 CD45 调节
  • 批准号:
    2072827
  • 财政年份:
    1996
  • 资助金额:
    $ 11.34万
  • 项目类别:

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