Novel roles for the DNA damage response kinase CHK1 in TCR/ITAM signaling

项目摘要 协调对DNA损伤的反应的细胞机制对于确保细胞 具有潜在有害缺陷的细胞不能在细胞周期中进展并促进恶性转化。 为此，ATR激活的CHK 1激酶在识别复制后在细胞核中具有关键功能 在停滞的DNA复制中，压力通过触发信号级联反应来中断细胞周期。但 这种激酶对在细胞核外的作用还不太清楚， 免疫应答以前没有被探索过。利用尖端的生物化学技术， 成像以及细胞和体内免疫学方法，将追求两个具体目标。目标1）定义 CHK 1与T细胞受体（TCR）信号分子之间的分子联系及其在T细胞 体内激活。目的2）评价CHK 1在免疫相关受体中的类似信号作用， 以确定其作用机制。这些研究预计将产生对角色的基本见解 对于CHK 1，迄今为止推测主要在细胞核中发挥作用，参与细胞质免疫受体信号传导 事件，并定义这些角色对免疫力的影响。这些研究的更广泛的影响包括新的 深入了解ATR和CHK 1抑制剂的潜在作用，目前正在癌症临床试验中进行评估， 免疫系统.这些见解可能有助于减轻这些药物的意外影响， 最大化靶向ATR/CHK 1或新的下游介质的潜力， 免疫系统 !

Project Summary The cellular machinery coordinating responses to DNA damage is critically important to ensure that cells with potentially deleterious defects do not progress through the cell cycle and promote malignant transformation. To this end, the ATR-activated CHK1 kinase has key functions in the nucleus upon recognition of replication stress at stalled DNA replication forks by triggering a signaling cascade that halts the cell cycle. However, the roles for this kinase pair outside the nucleus are less well understood, and a non-canonical function specific to the immune response has not been explored previously. Using cutting-edge biochemistry, super-resolution imaging, and cellular and in vivo immunology approaches, two specific aims will be pursued. Aim 1) To define the molecular connections between CHK1 and T cell receptor (TCR) signaling molecules and their roles in T cell activation in vivo. Aim 2) To evaluate analogous signaling roles for CHK1 in related receptors of the immune in order to pinpoint its mechanism of action. These studies are expected to yield fundamental insights into roles for CHK1, heretofore presumed to function primarily in the nucleus, in cytoplasmic immunoreceptor signaling events and define the impact of these roles on immunity. The broader implications of these studies include novel insights into potential effects of ATR and CHK1 inhibitors, currently under evaluation in cancer clinical trials, on the immune system. These insights may be beneficial in mitigating unexpected effects of these drugs and maximizing the potential to target ATR/CHK1 or novel downstream mediators therapeutically in diseases of the immune system. !