TR&D3: Metabolic Programming

TR

• 批准号: 10436872
• 负责人: JONATHAN D POWELL
• 金额: $ 31.89万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10436872
• 关键词: Adoptive Cell Transfers; Adoptive Transfer; Antigens; Biocompatible Materials; Cell Respiration; Cell Therapy; Cells; Clinical; Differentiation and Growth; Disease; Effector Cell; Engineering; Epigenetic Process; Explosion; FRAP1 gene; Fatty Acids; Generations; Glucocorticoids; Glutamine; Glycolysis; Goals; Hyperactivity; Immune response; Immune system; Immunologic Memory; Immunologics; Infection; Laboratories; Lipids; Malignant Neoplasms; Mediating; Memory; Metabolic; Metabolism; Mutate; Nucleic Acids; Pathway interactions; Phenotype; Phosphotransferases; Play; Proteins; Reagent; Regulation; Role; Serum; Specificity; System; T-Cell Activation; T-Lymphocyte; TSC2 gene; Therapeutic; base; cancer immunotherapy; cell growth; chimeric antigen receptor T cells; effector T cell; immune activation; immune function; immunoengineering; immunoregulation; in vivo; knock-down; mTOR inhibition; metabolic engineering; novel; prevent; programs; small molecule inhibitor; success; synthetic biology; tool development

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.

免疫工程的最终目标是利用免疫的精致专一性。 预防和治疗疾病的系统。然而，越来越清楚的是，细胞代谢 编程不仅是免疫细胞激活的结果，而且是 促进差异化和功能化。具有健壮效应器功能的细胞的产生密切相关 依赖于核酸、脂肪和蛋白质底物以及能量的产生。同样，坚持不懈 或者，免疫“记忆”的诱导依赖于新陈代谢的重新编程，从而为长期提供动力 生死存亡。在这种情况下，成功的免疫细胞工程将需要调制、编程甚至 对能量和底物生成代谢计划进行重新编程。最初是基于我们的研究 剖析mTOR通路在调节免疫反应中的作用我们的实验室已经定义了特定的 调节代谢程序的节点/目标，这是为效应器功能和长期持久性提供燃料所必需的。 研发3试图利用这些发现来针对这些关键节点来设计新陈代谢 对单元进行重新编程，从而最大化功能和持久性。为此，我们将开展以下工作 目的：目的：目标1.利用合成生物学，通过以下方式提高mTORC1活性的基因工程细胞 敲除/敲除/突变TSC2，导致增强的效应器功能，其特征是更健壮 糖酵解重编程。可交付：创建一个重新编程的“库存”效应细胞，然后可以 针对一系列细胞疗法进行了改进。目的2.通过调节谷氨酰胺代谢，形成生长和 促进细胞生成的分化条件，表观遗传编程使其在 在体内通过转移，并在重新挑战时最大限度地做出反应。交付成果：代谢性 生产健壮持久的效应器细胞的优化培养基。目标3.基于关于以下方面的新发现 SGK1促进记忆T细胞表型和效应T细胞表型及开发小分子抑制物的能力 能够在体内和体外对T细胞进行代谢重新编程的SGK1。交付内容：小分子 用于提高过继细胞疗法疗效的抑制剂。