PI3K signaling in regulation of CD8 T cell senescence and death

PI3K信号传导调控CD8 T细胞衰老和死亡

• 批准号: 9275611
• 负责人: Carrie L. Lucas
• 金额: $ 24.9万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9275611
• 关键词: Address; Affect; Animals; Aplastic Anemia; Apoptosis; Apoptotic; Autoimmunity; Biochemical; Blast Cell; CASP8 gene; CD8B1 gene; Cell Aging; Cell Death; Cell Proliferation; Cell physiology; Cells; Cessation of life; Chronic; Clinical; Cytokine Receptors; DNA; DNA Damage; Data; Development; Development Plans; Disease; Environment; FRAP1 gene; Failure; Foundations; Genes; Goals; Growth; Homeostasis; Human; Immune; Immune System Diseases; Immune response; Immune system; Immunologic Deficiency Syndromes; In Vitro; Infection; Inflammatory Bowel Diseases; Interleukin-2; Investigation; Knowledge; Leukocytes; Life; Link; Lipids; Lymphatic Diseases; Lymphopenia; Lymphoproliferative Disorders; MAP3K7 gene; Malignant Neoplasms; Mediating; Memory; Metabolism; Mitogens; Molecular; Mus; Mutation; Nuclear; Nuclear Translocation; Pathology; Pathway interactions; Patients; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositols; Phosphorylation; Phosphotransferases; Play; Population; Predisposition; Process; Protein Biosynthesis; RNA-Directed DNA Polymerase; Recurrence; Regulation; Research Personnel; Resources; Risk; Role; Severity of illness; Signal Pathway; Signal Transduction; Solid; T cell regulation; T-Cell Proliferation; T-Cell Receptor; T-Lymphocyte; Telomerase; Telomere Maintenance; Telomere Shortening; Training; Transplantation; Viremia; abstracting; base; career; career development; cell behavior; cell growth; cytokine; gain of function mutation; graft vs host disease; human disease; immunoregulation; in vivo; insight; mouse model; novel; novel therapeutics; receptor; response; senescence; telomere; tenure track; therapeutic target

DESCRIPTION (provided by applicant): Project Summary/Abstract The immune system provides a critical defense against life-threatening infections, but with this capability of robust immune responses comes the risk of immune dysfunction that can itself cause life- threatening diseases. Failure of T cell homeostasis occurs when T cell proliferation, senescence, and/or death are dysregulated, and this leads to diseases including lymphoproliferative disease, lymphopenia, aplastic anemia, and autoimmunity, among others. The phosphoinositide 3-kinase (PI3K) signaling pathway is an important pathway to understand in T cell homeostasis and function since it plays a prominent role in promoting cell growth, changes in metabolism, and proliferation in response to growth factors and mitogens. We have recently described patients with severe immune dysregulation caused by hyperactive PI3K signaling in leukocytes. These patients suffer from immunodeficiency and lymphoproliferative disease caused by heterozygous, gain-of-function mutations in the leukocyte-restricted p110? PI3K. T cells from these patients show (1) defective proliferative responses, which mechanistically link to PI3K-driven terminal differentiation, telomere shortening, and senescence, and (2) increased susceptibility to TCR restimulation-induced cell death, which we hypothesize is due to augmented pro-apoptotic signaling through PKC. Using the valuable resource of these patient T cells together with in vivo mouse models, the overall goal of this proposal is to investigate the role of PI3K signaling in CD8 T cell senescence (Aim 1) and death (Aim 2). The results of these investigations will enable a better understanding PI3K signaling in immune dysregulation that will aid in reaching the long-term goal of devising superior clinical approaches to immunomodulation for immunodeficiencies, lymphoproliferative diseases, lymphopenia, transplantation, and autoimmunity. Furthermore, completing the proposed career development plan as I address these scientific aims will provide a solid foundation for launching a successful career as an independent investigator.

描述（由申请人提供）：项目摘要/摘要免疫系统为威胁生命的感染提供了重要的防御，但具有强大的能力 免疫反应带来了免疫功能障碍的风险，它本身会引起生命危害生命的疾病。当T细胞增殖，衰老和/或死亡失调时，T细胞体内平衡的失败会发生，这导致包括淋巴细胞增生性疾病，淋巴细胞减少症，性障碍性贫血和自身免疫性在内的疾病。磷酸肌醇3-激酶（PI3K）信号传导途径是T细胞稳态和功能中理解的重要途径，因为它在促进细胞生长，代谢变化以及对生长因子和有差点元的响应中起着重要作用。我们最近描述了由白细胞中过度活跃的PI3K信号引起的严重免疫失调的患者。这些患者患有由白细胞限制的P110中的杂合，功能收益突变引起的免疫缺陷和淋巴增生性疾病？ PI3K。来自这些患者的T细胞显示（1）有缺陷的增生反应，从机械上讲，这与PI3K驱动的末端分化，端粒缩短和衰老以及（2）增加对TCR诱导的细胞死亡的敏感性增加，我们假设这是由于通过PKC通过PKC增强的。使用这些患者T细胞的宝贵资源以及体内小鼠模型，该提案的总体目标是研究PI3K信号传导在CD8 T细胞衰老中的作用（AIM 1）和死亡（AIM 2）。这些研究的结果将使免疫失调中的PI3K信号传导更好，这将有助于实现为免疫缺陷，淋巴细胞增生性疾病，淋巴细胞增多症，移植和自身免疫性的卓越临床方法的长期目标。此外，在我解决这些科学目标时，完成了拟议的职业发展计划，将为启动成功的职业生涯提供稳固的基础。