Role of glutamine metabolism in Dendritic Cell Development

谷氨酰胺代谢在树突状细胞发育中的作用

• 批准号: 10735230
• 负责人: Malay Haldar
• 金额: $ 32.5万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10735230
• 关键词: Affect; Amino Acids; Antigen Presentation; Antigen-Presenting Cells; Antioxidants; Autoimmune Diseases; Blood; Bone Marrow; CDC2 gene; Cell Differentiation process; Cell Proliferation; Cell Survival; Cell physiology; Cells; ChIP-seq; Chromatin; Consumption; Cross Presentation; DNA; DNA Methylation; Data; Dendritic Cells; Detection; Development; Drug or chemical Tissue Distribution; Enzymes; Epigenetic Process; Flow Cytometry; Frequencies; Funding Mechanisms; GLS2 gene; Gatekeeping; Gene Expression Regulation; Genes; Genetic; Glutamates; Glutaminase; Glutamine; Glutathione; Growth; Guidelines; Hematopoietic stem cells; Human; Immune response; Immune system; Immunity; Immunotherapeutic agent; Infiltration; Inflammation; Innate Immune Response; Isoenzymes; Link; Malignant Neoplasms; Mass Spectrum Analysis; Measures; Mediating; Metabolic; Metabolism; Molecular; Myelogenous; NADP; Natural Immunity; Organ Transplantation; Outcome; Oxidative Stress; Pathologic; Pathologic Processes; Pathway interactions; Pattern recognition receptor; Peripheral; Play; Process; Production; Promoter Regions; Property; Reactive Oxygen Species; Regulation; Research; Role; Stress; T-Lymphocyte; Testing; Tissue Differentiation; Tissues; Vaccines; Virus; Work; adaptive immune response; alpha ketoglutarate; amino acid metabolism; antagonist; bisulfite sequencing; cofactor; coping; demethylation; epigenetic regulation; hematopoietic differentiation; histone methylation; immune modulating agents; immunoregulation; in vitro Model; in vivo; lymphoid organ; novel; pathogen; pharmacologic; progenitor; response; single-cell RNA sequencing; small molecule inhibitor; transcription factor; tumor-immune system interactions; uptake

Project Summary Conventional dendritic cells (CDC) play a central role in protective immunity by connecting innate and adaptive immune responses. CDCs can distinguish `self' from `non-self' (example pathogen) or `altered-self' (example cancer) through specialized pattern recognition receptors and help orchestrate the appropriate adaptive immune response. CDC1 and CDC2 are the two major subsets of CDCs with CDC1s having the unique capacity to cross- present antigens that is critical for immunity against viruses and cancer. Circulating precursors of CDCs (Pre- CDCs) infiltrate tissue where they differentiate into CDC1 and CDC2. The relative distribution of these CDC subsets differ between tissue types and under pathological conditions, suggesting a role of tissue microenvironment in Pre-CDC differentiation. What factors in the tissue microenvironment might regulate this process, however, remains poorly understood. Our preliminary studies show that CDC1 differentiation is regulated by local availability of the amino acid glutamine through its metabolic conversion into glutamate. Glutamine uptake and utilization increases significantly in rapidly proliferating cells or during catabolic stress, potentially creating a glutamine deficient local microenvironment. Hence, we hypothesize that metabolic adaptations in tissue alters local CDC1 differentiation by modulating glutamine levels. In this proposal, we seek to understand which steps of CDC1 differentiation is regulated by glutamate and its underlying molecular mechanism. We will focus on epigenetic regulation of gene expression and oxidative stress as potential pathways by which glutamate mediates this effect. Findings from the proposed work can potentially open new lines of research linking tissue metabolic adaptations to its immune microenvironment.

项目概要 传统树突状细胞 (CDC) 通过连接先天性和适应性在保护性免疫中发挥核心作用 免疫反应。 CDC 可以区分“自我”和“非自我”（例如病原体）或“改变的自我”（例如 癌症）通过专门的模式识别受体并帮助协调适当的适应性免疫 回复。 CDC1 和 CDC2 是 CDC 的两个主要子集，其中 CDC1 具有独特的交叉能力。 呈现对病毒和癌症免疫至关重要的抗原。 CDC 的循环前体（Pre- CDC）浸润组织并分化为 CDC1 和 CDC2。这些CDC的相对分布 子集在组织类型和病理条件下有所不同，表明组织的作用 Pre-CDC分化的​​微环境。组织微环境中的哪些因素可能对此进行调节 然而，人们对这个过程仍然知之甚少。我们的初步研究表明CDC1分化是 通过代谢转化为谷氨酸，受氨基酸谷氨酰胺的局部可用性调节。 在快速增殖的细胞中或在分解代谢应激期间，谷氨酰胺的摄取和利用显着增加， 可能会造成谷氨酰胺缺乏的局部微环境。因此，我们假设代谢 组织的适应通过调节谷氨酰胺水平来改变局部 CDC1 分化。在本提案中，我们寻求 了解 CDC1 分化的哪些步骤是受谷氨酸及其潜在分子调节的 机制。我们将重点关注基因表达和氧化应激的表观遗传调控潜力 谷氨酸介导这种作用的途径。拟议工作的发现可能会开辟新的领域 将组织代谢适应与其免疫微环境联系起来的研究路线。