CD5 REGULATION OF CK2 IN T CELLS OF DIFFERENT AGES

这项建议将研究CD 5作为T细胞调节因子的作用。 受体（TCR）诱导的活化及其与发育和 衰老CD 5是TCR相关分子，在T细胞中很早就表达 胸腺细胞和成熟胸腺细胞功能差异的发育 外周血T细胞它似乎是TCR的负调节剂- 胸腺细胞中的依赖性信号传导，而它通过 成熟T细胞中的TCR。我们的数据表明， CD 5缺陷型小鼠胸腺细胞与CD 3介导的缺失相比 野生型对照强调了CD 5在T细胞发育过程中的作用。 我们现在已经表明，这种差异的潜在机制 信号传导是通过丝氨酸/苏氨酸激酶的差异调节 CK2。CK 2是一种重要的激酶，通过调节细胞生长、分化 几种信号转导途径，直接与CD 5相关， 受受体调控。CD 5对CK 2的调节依赖于 T细胞的发育阶段和年龄。教条是CK 2 只涉及远端信号事件，然而，我们的数据现在 显然不是这么回事我们认为，CD 5依赖性调节 CK 2是CD 5差异调节T细胞的主要机制 生物学与发育和衰老我们建议定义体内作用 通过用CD 5重建CD 5缺陷小鼠的CD-5依赖性调节 缺乏激活CK 2能力的转基因，从而产生 本质上是一只信号缺陷的老鼠我们将使用这个模型来定义 通过CK 2调节的CD 5依赖性信号传导的变化与 老化和发展。这种方法将使我们能够检查函数 这些分子的完全缺失可以通过补偿性变化来实现 在发展过程中。建议的具体目标是：（1） 表征CD 5和潜在的共分子的性质， 对于CK 2激活，（2）确定CD 5依赖性CK 2的特异性靶点 激活和（3）建立体内表型的CD 5 缺陷（-/-）小鼠和用改变的CD 5重建的CD 5-/-小鼠。我们 我相信这个建议对于理解 调节T细胞的发育和激活，并为定义 衰老相关的T细胞信号传导的变化和耐受性的破坏。小说 然后可以设计治疗策略来靶向这些途径。

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.