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

描述（由申请人提供）：信号传导机制的分析推动了对生物调节的基本见解以及可能的治疗干预的重要靶点。适应性免疫和自身免疫性疾病是由调节CD 4和CD 8 T细胞分化和命运选择之间的平衡的信号转导途径以及不同亚群产生免疫记忆的能力决定的。通过PI 3-激酶（PI 3 K）引发的信号部分地由促存活激酶Akt中继，其活化和下游靶标如哺乳动物雷帕霉素靶标（mTOR）调节存活和增殖。雷帕霉素是一种可用于移植医学的免疫抑制药物，其功能等同于mTOR抑制，但最近的研究结果表明，mTOR通过至少两种相互排斥的多蛋白复合物发挥作用。第一个是mTORC 1，对雷帕霉素敏感，调节蛋白质翻译和细胞生长。然而，第二类mTOR复合物，称为mTORC 2，相对雷帕霉素耐药，抑制作用取决于药物的有效浓度。虽然mTORC 1的信号传导和生物学已经被广泛研究，但对mTORC 2在正常细胞生理学中的作用知之甚少，在免疫系统细胞中也一无所知。关于mT 0 RC 2在免疫中的功能（如果有的话）、任何此类功能的机制或其与Akt与PKC途径的关系以及mT 0 RC 2的缺乏是否会减轻淋巴细胞中由PTEN缺失引起的异常的证据都是未知的。令人兴奋的迹象表明，雷帕霉素在调节CTL的效应子和记忆状态之间的平衡中具有复杂的作用，但在这方面对辅助谱系一无所知，也没有深入了解mTORC 2如何与雷帕霉素对CTL记忆的影响有关。因此，理解mTORC 2复合物的功能作为mTOR信号传导在免疫和记忆中的新前沿的一部分的需要特别大。基于我们的初步发现，该提议的中心假设是（i）mTORC 2信号传导复合物介导成熟T细胞获得完全和适当平衡的功能能力，以及（ii）它根据生物靶向过程使用不同的下游信号中继来调节它们参与免疫和自身免疫的特性和能力。为了验证中心假设并阐明相关机制，我们提出定义mTORC 2在T细胞介导的初级和回忆免疫中的作用（Aim 1），阐明mTORC 2通过Akt-和PKC-8的HM修饰影响T辅助细胞分化的机制（Aim 2），并剖析mTORC 2和PTEN在调节T细胞中的相互作用（Aim 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力和CD 4 T细胞命运，以及（ii）确定通过Akt和PKC信号传导影响这类T细胞获得的基因表达程序平衡的新机制，从而提供更具选择性的治疗靶向的潜力。

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.