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

基本信息

批准号：
9338299
负责人：
Carrie L. Lucas
金额：
$ 24.82万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
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/9338299
关键词：
Address Affect Animals Aplastic Anemia Apoptosis Apoptotic Autoimmunity Biochemical Blast Cell CASP3 gene CASP8 gene CD8-Positive T-Lymphocytes 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 Factor Homeostasis Human Hyperactive behavior Immune Immune System Diseases Immune System and Related Disorders Immune response Immune system Immunologic Deficiency Syndromes In Vitro Infection Inflammatory Bowel Diseases Interleukin 2 Receptor 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 Proliferation T-Cell Receptor T-Lymphocyte Telomerase Telomere Maintenance Telomere Shortening Training Transplantation Viremia 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

项目摘要

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/摘要免疫系统提供了针对危及生命的感染的关键防御，但具有强大的防御能力免疫反应带来免疫功能障碍的风险，免疫功能障碍本身可能导致危及生命的疾病。当 T 细胞增殖、衰老和/或死亡失调时，T 细胞稳态就会失败，从而导致包括淋巴细胞增殖性疾病、淋巴细胞减少症、再生障碍性贫血和自身免疫等在内的疾病。磷酸肌醇 3-激酶 (PI3K) 信号通路是了解 T 细胞稳态和功能的重要通路，因为它在促进细胞生长、代谢变化以及响应生长因子和有丝分裂原的增殖方面发挥着重要作用。我们最近描述了由于白细胞中 PI3K 信号传导过度活跃而导致严重免疫失调的患者。这些患者患有免疫缺陷和淋巴细胞增殖性疾病，这些疾病是由白细胞限制性 p110? 杂合、功能获得性突变引起的。 PI3K。这些患者的 T 细胞表现出 (1) 有缺陷的增殖反应，这在机制上与 PI3K 驱动的终末分化、端粒缩短和衰老有关，以及 (2) 对 TCR 再刺激诱导的细胞死亡的敏感性增加，我们假设这是由于通过 PKC 的促凋亡信号传导。利用这些患者 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（目标 1）和死亡（目标 2）中的作用。这些研究的结果将有助于更好地了解免疫失调中的 PI3K 信号传导，从而有助于实现设计针对免疫缺陷、淋巴细胞增殖性疾病、淋巴细胞减少症、移植和自身免疫的免疫调节的卓越临床方法的长期目标。此外，在我实现这些科学目标时完成拟议的职业发展计划将为作为一名独立研究者开启成功的职业生涯奠定坚实的基础。