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

DNA 损伤反应激酶 CHK1 在 TCR/ITAM 信号传导中的新作用

• 批准号: 10330648
• 负责人: Carrie L. Lucas
• 金额: $ 3.51万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10330648
• 关键词: Ablation; Address; Affect; Antigens; Area; Autoimmune Diseases; B-Cell Antigen Receptor; B-Lymphocytes; Biochemistry; CHEK1 gene; CHEK2 gene; CXCL12 gene; Cancer Patient; Cell Cycle; Cell Death; Cell Nucleus; Cells; Clinical; Clinical Trials; Complex; Consensus; Cytoplasm; DNA Damage; DNA Repair; DNA replication fork; Data; Defect; Dependence; Development; Ensure; Epidermal Growth Factor Receptor; Evaluation; Event; Exhibits; FCGR3B gene; Failure; Family; Fc Receptor; Fibroblasts; Future; Genetic; Genomics; Hematopoietic; Human; ITAM; Image; Immune System Diseases; Immune response; Immune signaling; Immune system; Immunity; Immunologic Receptors; Immunology; Infection; Investigation; KLRD1 gene; Knowledge; Ligation; Link; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of ovary; Maps; Mediator of activation protein; Molecular; Mus; NK Cell Activation; Natural Killer Cells; Pathway interactions; Pharmaceutical Preparations; Phosphatidylinositols; Phosphorylation; Phosphotransferases; Proliferating; Proteins; Receptor Activation; Receptor Cell; Receptor Signaling; Regulation; Resolution; Role; Serine; Signal Transduction; Signaling Molecule; Signaling Protein; Site; Surveys; T cell response; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Threonine; ZAP-70 Gene; adaptive immunity; cancer clinical trial; cancer risk; experience; experimental study; immune activation; immune function; in vivo; inhibitor/antagonist; insight; novel; public health relevance; ras Guanine Nucleotide Exchange Factors; receptor; recruit; replication stress; response; scaffold

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. !

项目摘要 细胞机械协调对DNA损伤的响应至关重要，以确保细胞 潜在的有害缺陷不会在整个细胞周期中进展并促进恶性转化。 为此，ATR激活的CHK1激酶在识别复制后具有关键功能 停滞的DNA复制叉处的应力通过触发阻止细胞周期的信号传导级联反应。但是， 该细胞核外的这种激酶对的作用知之甚少，并且特定于非典型的功能 以前尚未探索免疫反应。使用尖端生物化学，超分辨率 成像，细胞和体内免疫学方法，将追求两个具体的目标。目标1）定义 CHK1和T细胞受体（TCR）信号分子之间的分子连接及其在T细胞中的作用 在体内激活。目标2）评估CHK1在免疫中相关受体中的类似信号传导作用 为了查明其作用机理。预计这些研究将对角色产生基本的见解 对于CHK1，迄今为止主要在细胞核中，在细胞质免疫受体信号传导中起作用 事件并定义这些作用对免疫的影响。这些研究的更广泛含义包括新颖 对目前在癌症临床试验中评估的ATR和CHK1抑制剂的潜在影响的见解， 免疫系统。这些见解可能有益于减轻这些药物的意外影响，并 最大化靶向ATR/CHK1或新型下游介体治疗的潜力 免疫系统。 呢