TR&D3: Metabolic Programming

基本信息

批准号：
10223295
负责人：
JONATHAN D POWELL
金额：
$ 31.58万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
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/10223295
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

项目摘要

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独家特异性预防和治疗疾病的系统。但是，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，而且是不可或缺的组成部分促进分化和功能。具有健壮效应子功能的细胞的产生密切取决于核酸，脂质和蛋白质底物以及能量的产生。同样，持久性或免疫学“记忆”的诱导取决于代谢重编程长期燃料生存。在这种情况下，免疫细胞的成功工程将需要调制，编程甚至重新编程能量和底物生成代谢程序。最初是基于我们的研究剖析MTOR途径在调节免疫反应中的作用，我们的实验室已定义了特定的节点/目标以调节为燃料效应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针对这些关键节点，以设计代谢重新编程细胞，从而最大化功能和持久性。为此，我们将追求以下目的：AIM 1。采用合成生物学，遗传性自我的细胞具有增强的MTORC1活性击倒/熄灭/突变TSC2，导致效应子功能增强，其特征是更健壮糖酵解重编程。可交付：创建重编程的“库存”效应器单元，然后可以是修改为一系列细胞疗法。 AIM 2。通过控制谷氨酰胺代谢，配方奶的生长和分化条件，促进细胞的产生，表观遗传编程以持续存在经过体内转移，并对补偿进行最大的反应。可交付：代谢优化的培养基可产生稳健和持续的效应细胞。目标3。基于有关的新发现 SGK1促进记忆和效应T细胞表型的能力，发展小分子抑制剂 SGK1可以代谢重新编程的T细胞既是体内又是体内的。可交付：小分子抑制剂以提高过继细胞疗法的效率。