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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要传统的树突状细胞（CDC）通过连接先天和适应性在保护性免疫中起着核心作用免疫反应。 CDC可以将“自我”与“非自我”（示例病原体）或````'''''（示例）区分开癌症）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CDC1的CDC的两个主要子集，具有独特的交叉能力目前对抗病毒和癌症免疫至关重要的抗原。 CDC的循环前体（前 CDCS）浸润组织，它们分化为CDC1和CDC2。这些CDC的相对分布组织类型和病理条件下的子集不同，表明组织的作用 CDC前分化的微环境。组织微环境中的哪些因素可能会调节这一点然而，过程仍然知之甚少。我们的初步研究表明，CDC1的分化是由氨基酸谷氨酰胺通过代谢转化为谷氨酸的局部可用性调节。在快速增殖的细胞或分解代谢应激中，谷氨酰胺的摄取和利用率显着增加，可能会产生谷氨酰胺不足的局部微环境。因此，我们假设这种代谢组织中的适应通过调节谷氨酰胺水平来改变局部CDC1的分化。在此提案中，我们寻求要了解CDC1分化的哪些步骤受谷氨酸及其基础分子调节机制。我们将重点介绍基因表达和氧化应激的表观遗传调节谷氨酸介导这种作用的途径。提议的工作的发现可能会开放新的将组织代谢适应与其免疫微环境联系起来的研究线。