TR&D3: Metabolic Programming

免疫工程的最终目标是利用免疫系统的特异性， 预防和治疗疾病。然而，越来越清楚的是， 编程不仅仅是免疫细胞激活的结果，而是免疫系统的一个组成部分。 促进分化和功能。具有强大效应子功能的细胞的产生与细胞生长密切相关。 这取决于核酸、脂质和蛋白质底物以及能量的产生。同样， 或者免疫“记忆”的诱导依赖于代谢重编程， 生存在这种情况下，免疫细胞的成功工程化将需要调节、编程甚至是免疫细胞的基因工程化。 能量和底物生成代谢程序的重新编程。最初基于我们的研究 我们的实验室通过分析mTOR通路在调节免疫应答中的作用， 节点/目标，以调节燃料效应器功能和长期持久性所必需的代谢编程。 TR&D 3试图利用这些发现来靶向这些关键节点，以设计代谢 重新编程细胞，从而最大限度地发挥功能和持久性。为此，我们将采取以下行动： 目标：目标1。采用合成生物学，通过基因工程技术， 敲低/敲除/突变TSC 2，导致增强的效应子功能，其特征在于更稳健的 糖酵解重编程可重编程的：产生一种重编程的“储备”效应细胞，然后可以被 为一系列细胞疗法做了改造目标2.通过调节谷氨酰胺代谢， 促进表观遗传编程细胞生成的分化条件， 在体内过继转移，并在再激发时最大限度地响应。可代谢：代谢 用于产生稳健和持久的效应细胞的优化培养基。目标3。基于新的发现， SGK 1促进记忆和效应T细胞表型能力、产生小分子抑制剂 SGK 1可以在体外和体内代谢重编程T细胞。可降解：小分子 抑制剂，以增强连续性细胞疗法的功效。

The ultimate goal of immune-engineering is to harness the exquisite specificity of the immune system to prevent and treat disease. However, it is becoming increasingly clear that cellular metabolic programming is not merely a consequence of immune cell activation but rather an integral component of promoting differentiation and function. The generation of cells with robust effector function is intimately dependent upon the generation of nucleic acid, lipid and protein substrates, and energy. Likewise, persistence or the induction of immunologic “memory” is dependent upon metabolic reprogramming that fuels long term survival. In this context successful engineering of immune cells will entail modulation, programming and even reprogramming of energy and substrate-generating metabolic programs. Initially based on our studies dissecting the role of the mTOR pathway in regulating immune responses our lab has defined specific nodes/targets to regulate metabolic programming necessary to fuel effector function and long term persistence. TR&D 3 seeks to exploit these findings to target these critical nodes in order to engineer metabolic reprogramming of cells, thus maximizing function and persistence. To this end we will pursue the following Aims: Aim 1. Employing synthetic biology, genetically egineer cells with enhanced mTORC1 activity by knocking down/out/mutating TSC2, leading to enhanced effector function characterized by more robust glycolytic reprogramming. Deliverable: The creation of a reprogrammed “stock” effector cell that can then be modified for an array of cellular therapies. Aim 2. By regulating glutamine metabolism, formulate growth and differentiation conditions that promote the generation of cells epigenetically programmed to persist when adoptively transferred in vivo and to maximally respond upon rechallenge. Deliverable: Metabolically optimized media for producing robust and persistent effector cells. Aim 3. Based on novel findings regarding the ability of SGK1 to promote both a memory and effector T cell phenotype, develop small molecule inhibitors of SGK1 that can metabolically reprogram T cells both ex vivo and in vivo. Deliverable: Small molecule inhibitors to enhance efficacy of Adoptive Cellular Therapy.