p53-mediated dead cell clearance in response to DNA damage and tumorigenesis

p53 介导的死细胞清除响应 DNA 损伤和肿瘤发生

• 批准号: 9300883
• 负责人: SAM W LEE
• 金额: $ 36.8万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9300883
• 关键词: Antitumor Response; Apoptosis; Apoptotic; Autoantigens; Autoimmunity; Cell Death; Cell membrane; Cell model; Cell physiology; Cells; Cessation of life; Chronic; Coculture Techniques; DNA Damage; Data; Databases; Death Domain; Development; Disease; Eating; Environment; Event; Excision; Failure; Fostering; Gene Targeting; Generations; Genotoxic Stress; Health; Human; Immune; Immune Tolerance; Immune response; Immunity; Immunoglobulins; Immunologic Surveillance; Immunologics; In Vitro; Inflammation; Investigation; Knockout Mice; Lead; Life; Ligands; Link; Maintenance; Malignant Neoplasms; Mediating; Modeling; PDCD1LG1 gene; Pathway interactions; Phagocytes; Phagocytosis; Phase; Physiological; Process; Protein Family; Protein p53; Role; Signal Transduction; Stress; System; T cell response; T-Lymphocyte; TP53 gene; Testing; Tissues; base; cancer cell; cancer therapy; cytotoxicity; immune activation; immune checkpoint; in vivo; inhibitor/antagonist; member; mouse model; neoplastic cell; receptor; response; tumor; tumor progression; tumorigenesis

Project Summary Programmed cell death/apoptosis occurs throughout life in all tissues of the body and more than a billion of cells die everyday as part of normal processes. Thus rapid and efficient clearance of cell corpses is a vital prerequisite for homeostatic maintenance of tissue health. Failure to clear dying cells can lead to the accumulation of autoantigens in tissues that foster diseases such as cancer, chronic inflammation, autoimmunity and developmental abnormalities. High level of cell death can occur within tumor environment in cancer therapy, and the mechanisms through which dying tumor cells are cleared influence tumor-specific immunity. Thus, manipulation of the immunological context of dead cell removal has great potential for the control of tumor progression and generation of an antitumor response, which is still an outstanding issue and understanding this specific mechanism warrants investigation. Enormous efforts have been made toward understanding various mechanisms of tumor suppressor p53-mediated cell death/apoptosis. However, the involvement of p53 in post- apoptosis has not been implicated until now. In this application, we identified a first post- apoptotic target gene of p53, death domain1α, DD1α, which is highly responsive to genotoxic stresses/DNA damage. We found that p53 controls apoptotic cell clearance of through its target DD1α, suggesting that p53 promotes both the pro-apoptotic pathway and the post-apoptotic events. Moreover, DD1α appears to function as a negative immune-checkpoint regulator that modulates immune responses/T cell function, suggesting the role of DD1α in immune tolerance. DD1α has similarity with several members of the immunoglobulin superfamily with the IgV domain, including TIM family proteins and immune checkpoint co-inhibitors PD-1 and PD-L1. The public database indicates that expression of DD1α is increased in multiple human cancers, implicating its immune modulating function in cancer. Based on these data, we propose two major aims focused on mechanisms of understanding the roles of a newly found post-apoptotic target of p53 and investigating the potential to enhance the anti-tumor immune responses.

项目摘要 程序性细胞死亡/凋亡发生在身体的所有组织中，都超过 作为正常过程的一部分，每天有十亿个细胞死亡。快速有效的清除 细胞尸体是维持组织健康的重要先决条件。未能清除 垂死的细胞会导致自身抗原在组织中的组织积累，从而促进疾病 癌症，慢性感染，自身免疫性和发育异常。 高水平的细胞死亡可能发生在癌症治疗中的肿瘤环境中，并且 清除垂死的肿瘤细胞的机制会影响肿瘤特异性免疫。 那就是对去除死细胞的免疫学环境的操纵具有很大的潜力 控制肿瘤进展和抗肿瘤反应的产生，这仍然是 出色的问题和理解这种特定机制值得调查。 为理解肿瘤的各种机制而付出了巨大的努力 抑制剂p53介导的细胞死亡/凋亡。但是，p53参与后 直到现在尚未实施凋亡。在此应用程序中，我们确定了第一个职位 - p53，死亡域1α，dd1α的凋亡靶基因，对Genotoxy具有很高的反应 应力/DNA损伤。我们发现p53控制靶标的凋亡细胞清除率 DD1α，表明p53同时促进了凋亡途径和凋亡后途径 事件。此外，DD1α似乎是负免疫检查点调节剂， 调节免疫反应/T细胞功能，表明DD1α在免疫耐受性中的作用。 DD1α与多个免疫球蛋白超家族与IGV具有相似之处 结构域，包括TIM家族蛋白和免疫定位型共抑制剂PD-1和PD-L1。这 公共数据库表明，多种人类癌症中DD1α的表达增加， 隐含其在癌症中的免疫调节功能。基于这些数据，我们提出了两个 主要目标是理解新发现的凋亡后的作用机制 p53的靶标，并研究增强抗肿瘤免疫反应的潜力。