CD5 REGULATION OF CK2 IN T CELLS OF DIFFERENT AGES

这项提案将研究CD5作为T细胞调节因子的作用 受体(TCR)诱导的激活及其与发育和免疫功能的关系 衰老。TCR相关分子CD5很早就在T细胞中表达 胸腺细胞发育与成熟功能的差异 外周T细胞。它似乎是TCR的负调节因子- 胸腺细胞中的依赖信号，而它通过 成熟T细胞中的TCR。我们的数据证明了 CD5缺陷小鼠胸腺细胞对CD3介导的缺失的比较 野生型对照强调了CD5在T细胞发育中的作用。 我们现在已经证明了这种差异的一种潜在机制 信号是通过丝氨酸/苏氨酸激酶的不同调节来实现的 CK2。CK2是调节细胞生长、分化的关键蛋白 几个信号转导通路，直接与CD5和IS相关 受受体调节。CD5对CK2的调节依赖于 T细胞的发育阶段和年龄。教条一直是CK2 只涉及远端信号事件，然而，我们的数据现在 清楚地表明并非如此。我们提出CD5依赖的调控机制 CK2是CD5分化调节T细胞的主要机制 生物学与发育和衰老。我们建议定义在体内的作用 用CD5重组CD5缺陷小鼠对CD5依赖调控的研究 缺乏激活CK2能力的转基因，从而产生 本质上是一只信号缺陷的小鼠。我们将使用此模型来定义 与CK2调控相关的CD5依赖信号的变化 衰老和发育。这种方法将使我们能够检查函数 完全不存在的分子可以通过补偿性变化来要求 在开发过程中。该建议的具体目标是：(1) 描述CD5和潜在的共分子的性质，必要的 对于CK2的激活，(2)定义CD5依赖的CK2的特定靶点 和(3)建立CD5的体内表型 缺陷(-/-)小鼠和CD5-/-用改变的CD5重组。我们 我认为这项提议将对理解机制具有重要意义 调节T细胞的发育和激活，并为定义 与衰老相关的T细胞信号的变化和耐受性的打破。小说 然后，可以设计出针对这些途径的治疗策略。

This proposal will examine the role of CD5 as a regulator of T cell receptor (TCR) induced activation and its association with development and aging. CD5 a TCR associated molecule is expressed very early in T cell development with functions differentially in thymocytes and mature peripheral T cells. It appears to function as a negative regulator of TCR- dependent signaling in thymocytes whereas it potentiates activate via the TCR in mature T cells. Our data demonstrating the enhanced sensitivity of thymocytes from CD5 deficient mice to CD3 mediated deletion compared to wild type controls underscores the role of CD5 during T-cell development. We have now shown that a potential mechanism for this differential signaling is by the differential regulation of the serine/threonine kinase CK2. CK2 a critical kinase in regulating cell growth, differentiation via several signal transduction pathways, directly associates with CD5 and is regulated by the receptor. The regulation of CK2 by CD5 is dependent on the developmental stage and age of the T cell. The dogma had been that CK2 was involved only in distal signaling events, however, our data now clearly indicates otherwise. We propose that CD5-dependent regulation of CK2 is a major mechanism by which CD5 differentially regulates T cell biology with development and aging. We propose to define the in vivo role of CD-5 dependent regulation by reconstituting CD5 deficient mice with CD5 transgenes that lack the ability to activate CK2, thus generating essentially a signaling defective mouse. We will use this model to define changes in CD5-dependent signaling via CK2 regulation associated with aging and development. This approach will enable us to examine functions of molecules whose complete absence can be asked by compensatory changes during development. The specific aims of the proposal are (1) To characterize the properties of CD5, and potential co-molecules, essential for CK2 activation, (2) Define the specific targets for CD5 dependent CK2 activation with regard to and (3) Establish the in vivo phenotype of CD5 deficient (-/-) mice and CD5 -/- reconstituted with altered CD5. We believe that this proposal will be important in understanding mechanisms that regulate T cell development and activation and pave the way to define aging associated changes in T cell signaling and break of tolerance. Novel therapeutic strategies can then be devised to target these pathways.