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

描述(由申请人提供)：对信号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目标。获得性免疫和自身免疫性疾病是由信号转导通路决定的，这些信号转导通路调节CD4和CD8T细胞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PI3K启动的信号部分由促生存的蛋白激酶Akt传递，Akt的激活和下游靶标如哺乳动物靶标雷帕霉素(MTOR)调节生存和增殖。雷帕霉素是一种用于移植医学的免疫抑制药物，其作用被等同于mTOR抑制，但最近的研究发现，mTOR至少通过两类相互排斥的多蛋白复合体发挥作用。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复合体，称为mTORC2，对雷帕霉素相对耐药，抑制作用取决于药物的有效浓度。虽然mTORC2的信号和生物学已经被广泛研究，但对mTORC2在正常细胞生理中的作用知之甚少，在免疫系统的细胞中也是如此。关于mTORC2在免疫中的功能(如果有)的证据，任何这种功能的机制(S)或它与Akt和PKC通路的关系，以及mTORC2的缺乏是否可以减轻淋巴细胞中PTEN缺失引起的异常，都是未知的。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了复杂的作用，但对这方面的辅助谱系尚不清楚，也没有深入了解mTORC2与雷帕霉素对CTL记忆的影响。因此，了解mTORC2复合体作为mTOR信号在免疫和记忆中的新前沿的功能的必要性特别大。根据我们的初步发现，这一建议的中心假设是(I)mTORC2信号复合体介导成熟T细胞获得充分和适当平衡的功能，以及(Ii)它根据生物靶过程的不同下游信号传递调节其参与免疫和自身免疫的性质和能力。为了验证中心假设并阐明相关机制，我们建议定义mTORC2在T细胞介导的初级免疫和回忆免疫中的作用(目标1)，阐明mTORC2通过Akt-和PKC-8的HM修饰影响辅助性T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信号如何影响免疫和CD4T细胞命运，以及(Ii)确定通过Akt和PKC信号影响这类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可能性。

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.