Roles of rictor in mTOR signaling, differentiation & immune memory via Akt & PKC

rictor 在 mTOR 信号传导、分化中的作用

• 批准号: 8211997
• 负责人: Mark R Boothby
• 金额: $ 39万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-15 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8211997
• 关键词: 1-Phosphatidylinositol 3-Kinase; Acute; Affect; Alleles; Autoimmune Diseases; Autoimmunity; Biological; Biology; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Line; Cell physiology; Cells; Chronic; Clonal Expansion; Complex; Effectiveness; Equilibrium; Event; Gene Expression; Immune; Immune response; Immune system; Immunity; Immunologic Memory; Leukocytes; Light; Lipids; Lymphocyte; MHC Class I Genes; Malignant Neoplasms; Mature T-Lymphocyte; Measures; Mediating; Memory; Modification; Multiprotein Complexes; Normal Cell; Nuclear; Organ Transplantation; Outcome; PTEN gene; Pathway interactions; Pharmaceutical Preparations; Phase; Phosphorylation; Phosphotransferases; Play; Process; Property; Protein Isoforms; Protein Kinase C; Protein Tyrosine Phosphatase; Protein-Serine-Threonine Kinases; Proteins; Regulation; Research Proposals; Resistance; Role; Signal Transduction; Signal Transduction Pathway; Sirolimus; Specificity; T cell response; T memory cell; T-Lymphocyte; Testing; Therapeutic Intervention; Transgenic Organisms; Translations; Transplantation; Vaccines; Work; adaptive immunity; base; cell growth; frontier; immunological synapse; insight; mTOR protein; programs; protein complex; public health relevance; response; stem; therapeutic target; transcription factor; transplantation medicine

DESCRIPTION (provided by applicant): Analyses of signaling mechanisms drive fundamental insights into biological regulation as well as important targets for possible therapeutic interventions. Adaptive immunity and autoimmune disease are determined by signal transduction pathways that regulate the balance among differentiation and fate choices for CD4 and CD8 T cells, and the capacities of different subsets to generate immunological memory. Signals initiated through PI 3-kinases (PI3K) are relayed in part by the pro-survival kinase Akt, whose activation and downstream targets such as the mammalian Target of Rapamycin (mTOR) regulate survival and proliferation. Functions of rapamycin, an immune suppressive drug useful in transplantation medicine, had been equated with mTOR inhibition, but recent findings show that mTOR functions through at least two mutually exclusive classes of multiprotein complexes. The first, mTORC1, is rapamycin-sensitive and regulates aspects of protein translation and cellular growth. However, a second class of mTOR complex, termed mTORC2, is relatively rapamycin-resistant, with inhibition depending on the effective concentration of the drug. While the signaling and biology of mTORC1 have been investigated extensively, little is known about the roles of mTORC2 in normal cell physiology, and nothing in cells of the immune system. Evidence as to the function of mTORC2 in immunity (if any), the mechanism(s) for any such function or its relation to Akt vs. PKC pathways, and whether or not the lack of mTORC2 would mitigate abnormalities stemming from loss of PTEN in lymphocytes are all unknown. Exciting indications suggest complex roles of rapamycin in regulating a balance between effector and memory states for CTL, but nothing is known about the helper lineages in this regard, nor is there insight into how mTORC2 relates to the effect of rapamycin on CTL memory. Thus, the need to understand functions of the mTORC2 complex as part of new frontiers for mTOR signaling in immunity and memory is especially great. Based on our preliminary findings, the central hypotheses of this proposal are (i) that the mTORC2 signaling complex mediates the acquisition of full and appropriately balanced functional capabilities by mature T cells, and (ii) that it regulates their properties and capacity to participate in immunity and autoimmunity using different downstream signal relays depending on the biological target process. To test the central hypothesis and elucidate related mechanisms, we propose to define the roles of mTORC2 in T cell- mediated primary and recall immunity (Aim 1), elucidate mechanisms by which mTORC2 effects T helper differentiation via the HM modifications of Akt- and PKC-8 (Aim 2), and dissect the interplay between mTORC2 and PTEN in regulating T cells (Aim 3). The expected outcome of the proposed studies is that we will (i) change concepts and elucidate how mTOR signaling affects immunity and CD4 T cell fates, & (ii) identify new mechanisms by which signaling through Akt and PKC influence the balance of gene expression programs acquired by this class of T cells, thereby offering the potential for more selective therapeutic targeting. PUBLIC HEALTH RELEVANCE: The precise properties of a class of white blood cells called lymphocytes are central to the effectiveness of immune responses and vaccines but also cause autoimmune diseases and the rejection of organ transplants. Lymphocytes acquire their specific properties as a result of passing signals inside the cell, a feature exploited by effective but problematic immune suppressant drugs such as rapamycin. This research proposal seeks to understand key aspects of how proteins whose function is blocked by rapamycin function in immunity by regulating lymphocytes, and enhance understanding of the way in which vaccines work through 'immune memory'.

描述（由申请人提供）：信号机制的分析推动了对生物调节的基本认识以及可能的治疗干预的重要目标。适应性免疫和自身免疫性疾病是由信号转导途径决定的，这些信号转导途径调节 CD4 和 CD8 T 细胞的分化和命运选择之间的平衡，以及不同亚群产生免疫记忆的能力。通过 PI 3 激酶 (PI3K) 启动的信号部分由促生存激酶 Akt 传递，Akt 的激活和下游靶标（例如哺乳动物雷帕霉素靶标 (mTOR)）调节生存和增殖。雷帕霉素（一种用于移植医学的免疫抑制药物）的功能等同于 mTOR 抑制，但最近的研究结果表明 mTOR 通过至少两类相互排斥的多蛋白复合物发挥作用。第一个是 mTORC1，对雷帕霉素敏感，调节蛋白质翻译和细胞生长的各个方面。然而，第二类 mTOR 复合物，称为 mTORC2，对雷帕霉素相对耐药，其抑制作用取决于药物的有效浓度。虽然 mTORC1 的信号传导和生物学已被广泛研究，但人们对 mTORC2 在正常细胞生理学中的作用以及在免疫系统细胞中的作用知之甚少。关于 mTORC2 在免疫中的功能（如果有）、任何此类功能的机制或其与 Akt 与 PKC 通路的关系，以及 mTORC2 的缺乏是否会减轻淋巴细胞中 PTEN 缺失引起的异常，这些证据均未知。令人兴奋的迹象表明雷帕霉素在调节 CTL 效应器和记忆状态之间的平衡方面发挥着复杂的作用，但对这方面的辅助谱系一无所知，也没有深入了解 mTORC2 如何与雷帕霉素对 CTL 记忆的影响相关。因此，作为免疫和记忆中 mTOR 信号传导新领域的一部分，了解 mTORC2 复合物的功能的需求尤其迫切。根据我们的初步发现，该提案的中心假设是（i）mTORC2信号复合物介导成熟T细胞获得完整且适当平衡的功能能力，以及（ii）它根据生物靶标过程使用不同的下游信号中继来调节其参与免疫和自身免疫的特性和能力。为了检验中心假设并阐明相关机制，我们建议定义 mTORC2 在 T 细胞介导的初级和回忆免疫中的作用（目标 1），阐明 mTORC2 通过 Akt- 和 PKC-8 的 HM 修饰影响 T 辅助细胞分化的机制（目标 2），并剖析 mTORC2 和 PTEN 在调节 T 细胞中的相互作用（目标 3）。拟议研究的预期结果是，我们将 (i) 改变概念并阐明 mTOR 信号传导如何影响免疫和 CD4 T 细胞命运，以及 (ii) 确定通过 Akt 和 PKC 信号传导影响此类 T 细胞获得的基因表达程序平衡的新机制，从而为更具选择性的治疗靶向提供潜力。 公共卫生相关性：一类称为淋巴细胞的白细胞的精确特性对于免疫反应和疫苗的有效性至关重要，但也会导致自身免疫性疾病和器官移植排斥。淋巴细胞通过在细胞内传递信号而获得其特定特性，这一特性被雷帕霉素等有效但有问题的免疫抑制药物所利用。该研究计划旨在了解功能被雷帕霉素阻断的蛋白质如何通过调节淋巴细胞在免疫中发挥作用，并增强对疫苗通过“免疫记忆”发挥作用的方式的理解。