DRAK2, a kinase that regulates T cell activation

DAP激酶是与细胞死亡有关的丝氨酸/苏氨酸激酶。缺乏这类基因的小鼠 通过基因打靶获得Drak2家族，并对其淋巴细胞亚群和免疫反应性进行分析。 与使用异位过表达进行的研究相反，在激活诱导细胞死亡方面没有缺陷 在T淋巴细胞或其祖细胞中记录的。相反，来自Drak2-/-小鼠的T细胞表现出自主性 超敏反应，使它们相对独立于CD28介导的共- 刺激。实验被用来研究这种共刺激独立性对 免疫的诱导和调节。此外，受DRAK2调控的信号通路将是 调查过了。初步证据表明，它调节钙-钙调神经磷酸酶激活途径，并 实验将通过寻找生化相互作用和剂量依赖关系来验证这一假设 NFAT激活的调控。更一般地，建议进行实验来研究底物 DRAK2及影响DRAK2活性的上游介质。这些实验将阐明一部小说 免疫调节机制。一种调节T细胞敏感性的蛋白激酶的鉴定 激活构成了确定调节自身免疫、免疫的治疗药物的重要步骤 对感染性因素的反应，以及肿瘤免疫。

The DAP Kinases are serine/threonine kinases implicated in cell death. Mice deficient in a member of this family, Drak2, were produced by gene targeting and analyzed for lymphoid subsets and immune reactivity. Contrary to studies carried out using ectopic overexpression, no defect in activation induced cell death was noted in T lymphocytes or their progenitors. Instead, T cells from Drak2 -/- mice exhibit an autonomous hypersensitivity that renders them relatively independent of a requirement for CD28-mediated co- stimulation. Experiments are proposed to investigate the effect this co-stimulation independence has on induction and regulation of immunity. In addition, the signaling pathway regulated by DRAK2 will be investigated. Preliminary evidence indicates that it regulates the calcium-calcineurin activation pathway, and experiments will test this hypothesis by looking for biochemical interactions, and the dose-dependent regulation of NFAT activation. More generally, experiments are proposed to investigate the substrates of DRAK2 and the upstream mediators that affect DRAK2 activity. These experiments will elucidate a novel mechanism of immune regulation. The identification of a kinase that regulates the sensitivity of T cell activation constitutes in an important step in identifying therapeutics to regulate autoimmunity, immune responses to infectious agents, and tumor immunity.