The Role of the Adenosine Receptor in Th Cell Development and Function

腺苷受体在 Th 细胞发育和功能中的作用

• 批准号: 10063963
• 负责人: Peter B. Ernst
• 金额: $ 50.36万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-06 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10063963
• 关键词: ADORA2A gene; Address; Adenosine; Affect; American; Animal Model; Anti-Inflammatory Agents; Antigen-Presenting Cells; Antiinflammatory Effect; Bacteria; Bacteroides fragilis; Binding; Biology; Catabolism; Cells; Cicatrix; Colitis; Communities; Crohn' s disease; Data; Dendritic Cells; Development; Diagnostic tests; Disease; Disease susceptibility; Energy Metabolism; Environment; Enzymes; Equilibrium; Eragrostis; Frequencies; Funding; Gastrointestinal tract structure; Genes; Genomic approach; Glycolysis; Goals; Homeostasis; Human; Immune; Immune response; Immunobiology; Immunologics; Immunology; Immunotherapy; Impairment; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Intestines; Knockout Mice; Knowledge; Lymphocyte; Lymphoid; Lymphoid Cell; Maintenance; Mediating; Messenger RNA; Metabolic; Metabolism; Microbe; Modeling; Mucosal Immunity; Mucous Membrane; Mus; Organism; Oxidative Phosphorylation; Pathogenesis; Pathogenicity; Phenotype; Polysaccharides; Predisposition; Prevention; Production; Property; Purinergic P1 Receptors; Purines; Rag1 Mouse; Regulatory T-Lymphocyte; Role; Series; Shapes; Signal Transduction; Source; Testing; Therapeutic; Ulcerative Colitis; adenylate kinase; antimicrobial; chronic infection; cytokine; dysbiosis; experimental study; flexibility; functional genomics; gastrointestinal; glucose uptake; gut microbiota; immunoregulation; insight; microbial; microbial community; microbiome; microbiota; novel; pathobiont; purine metabolism; response; therapeutic development

ABSTRACT/SUMMARY Immunological homeostasis reflects a balance between the host response and the antigenic environment. In mucosal immunology, inflammatory bowel diseases (IBD), including ulcerative colitis or Crohn’s disease, reflect a disruption in homeostasis with exaggerated host responses to the local microbiota in genetically susceptible hosts. Our microbial communities are dynamic so regulatory Th cells induced in the periphery (pTreg) are important to maintain a flexible homeostasis with these diverse organisms. Many factors modify the metabolic balance that maintains homeostasis and Treg function. Relevant to this proposal, studies have associated a disruption in adenosine metabolism with IBD in humans and in animal models. Adenosine is a purine metabolite derived from ATP through its conversion to ADP and 5’AMP by CD39 while CD73 continues the metabolism to adenosine. As the production of ATP from dead cells or bacteria is pro-inflammatory, its catabolism to adenosine is one means to restrict inflammation. Adenosine has direct anti-inflammatory properties mediated primarily through the A2A adenosine receptor (A2AAR) expressed by lymphocytes as well as antigen presenting cells and innate lymphoid cells. Moreover, we present new findings suggesting that adenosine shifts the energy metabolism in Th cells in order to confer its anti-inflammatory effects. Other data show that the absence of adenosine initiates the expansion of pathogenic Th cells, a decrease in Treg, and selects for microbiota that transmit susceptibility to colitis. The hypothesis for this study is that adenosine is required to maintain immunological homeostasis in the digestive tract. More specifically, disrupting adenosine production or responsiveness impacts lymphoid cell fate that subsequently changes bacterial colonization, creates a dysbiosis and promotes inflammation. The broad objective of the project is to define the role of purine metabolism on the control of immunological homeostasis in the gut as addressed in the following interrelated Specific Aims: Aim 1: Identify how lymphoid-microbial homeostasis relies on adenosine. Aim 2: Determine how adenosine controls protective responses to microbiota Aim 3: Define the role of purine metabolism in controlling lymphoid cell fate. . The proposed experiments will explore novel aspects of immunological homeostasis. These studies will have a positive impact on the basic understanding of lymphoid cell plasticity and provide new knowledge that can be used to expedite the identification and development of therapeutic strategies for immune-mediated diseases.

摘要/摘要 免疫稳态反映了宿主反应与抗原环境之间的平衡。 在粘膜免疫学中，炎症性肠病（IBD），包括溃疡性结肠炎或克罗恩病， 反映出体内稳态的破坏，占主体对局部微生物群的反应一般的反应 易感宿主。我们的微生物群落是动态的，因此在周围诱导的调节性TH细胞 （Ptreg）对于这些潜水生物的柔性稳态很重要。许多因素修改了 维持体内平衡和Treg功能的代谢平衡。与该建议相关，研究有 在人类和动物模型中与IBD腺苷代谢的破坏相关联。腺苷是 嘌呤代谢产物从ATP转换为ADP，CD39衍生出5'AMP，而CD73继续进行 腺苷的代谢。由于死细胞或细菌的ATP产生是促炎的，因此 与腺苷的分解代谢是限制注射的一种方法。腺苷具有直接抗炎 也主要通过淋巴细胞表达的A2A腺苷受体（A2AAR）介导的特性 作为抗原呈现细胞和先天淋巴样细胞。此外，我们提出了新发现，表明 腺苷会改变TH细胞中的能量代谢，以赋予其抗炎作用。其他数据 表明缺乏腺苷会启动致病性TH细胞的扩张，Treg的降低和 选择对结肠炎传播敏感性的微生物群。这项研究的假设是腺苷是 需要在消化道中维持免疫稳态。更具体地说，破坏腺苷 产生或反应性会影响随后改变细菌定植的淋巴细胞脂肪， 产生营养不良并促进炎症。该项目的广泛目的是定义 嘌呤代谢对肠道免疫稳态的控制，如下 相互关联的具体目的： 目标1：确定淋巴微生物稳态如何依赖腺苷。 目标2：确定腺苷如何控制对菌群的保护性反应 AIM 3：定义纯代谢在控制淋巴样细胞命运中的作用。 提出的实验将探索免疫稳态的新方面。这些研究会 对淋巴样细胞可塑性的基本理解有积极影响，并提供新知识 可以用来加快对免疫介导的理论策略的识别和发展 疾病。