Determining the contribution of polyamine biosynthesis to the function of group 3 innate lymphoid cells in the gastrointestinal system

确定多胺生物合成对胃肠道系统第 3 组先天淋巴细胞功能的贡献

• 批准号: 10474523
• 负责人: Vincent Peng
• 金额: $ 4.3万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10474523
• 关键词: Activities of Daily Living; Adult; Affect; Aging; Anabolism; Anti-CD40; Antibodies; Arginine; Autoimmune; Autoimmunity; B-Lymphocytes; Bacteria; Biological Assay; Body Weight decreased; Bromodeoxyuridine; CCR6 gene; Cell physiology; Cells; Chemicals; Chromatin; Chronic; Citrobacter; Citrobacter rodentium; Colitis; Colon; Crohn' s disease; DL-alpha-Difluoromethylornithine; Data; Developed Countries; Developing Countries; Development; Disease Marker; Distal; Drug usage; Environment; Enzymes; Epithelial; Eukaryota; Exhibits; Flow Cytometry; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Histology; Homeostasis; Host Defense; Human; Immune; Immunofluorescence Microscopy; Impairment; In Vitro; Infection; Inflammatory; Inflammatory Bowel Diseases; Interleukin-17; Intestines; Laboratories; Light; Lymphocyte; Lymphoid; Lymphoid Cell; Lymphoid Follicle; Lymphoid Tissue; Malignant Neoplasms; Measures; Mediating; Metabolic; Metabolic Pathway; Metabolism; Modeling; Monitor; Mucous Membrane; Mus; Myeloid Cells; Neutrophil Infiltration; Ornithine Decarboxylase; Pathogenicity; Pathology; Play; Polyamine Synthesis Inhibition; Polyamines; Pre-Clinical Model; Production; Rag1 Mouse; Research; Research Proposals; Resistance; Role; Severity of illness; Shapes; Signal Transduction; Small Intestines; T-Lymphocyte; Therapeutic Intervention; Tissues; Translations; Tumor-infiltrating immune cells; Ulcerative Colitis; cytokine; dietary; enteric infection; enteric pathogen; experimental study; extracellular; gastrointestinal system; immunoregulation; in vivo; interleukin-22; intestinal homeostasis; metabolomics; monocyte; mouse model; new therapeutic target; response; single-cell RNA sequencing

Project Summary The objective of this research proposal is to define the role of polyamines in modulating intestinal innate lymphoid cell homeostasis. Innate lymphoid cells (ILC) play a crucial role in mucosal barrier integrity and resistance to pathogenic insult through the integration of environmental signals and rapid secretion of immunoregulatory cytokines. In the intestine, group 3 ILC (ILC3) are crucial in defense against pathogenic bacterial colonization. They play significant roles in promoting the barrier function of the epithelium, regulating intestinal myeloid cells, and inducing the formation of lymphoid tissue within the mucosa to orchestrate intestinal homeostasis. However, dysregulation of ILC3 drives intestinal autoimmunity and has been associated with chronic inflammatory bowel diseases (IBD). Although it is known that intestinal lymphocytes make numerous metabolic adaptations in order to function in the tissue, little is understood about the relationship between cellular metabolism and the various functions of ILC3. We have integrated single-cell RNA-sequencing data and untargeted metabolomics of intestinal ILC to identify a significant enrichment of polyamines and polyamine metabolic enzymes in ILC3. Furthermore, our preliminary data demonstrate a positive role for polyamines in supporting ILC3 proliferation and function. We propose to 1) evaluate the impact of intracellular polyamines on ILC3 function at steady state and 2) assess the contribution of ILC3-intrinsic polyamine metabolism in a preclinical model of colitis. We hypothesize that polyamines positively regulate ILC3 function and thus contribute to the immunopathological role of ILC3 in colitis. The proposed research plan will define an ILC3-intrinsic contribution of polyamines in enhancing their activity and potentiating colitis. If this is the case, these results will further our understanding of the metabolic adaptations of ILC3 as well as the potential role for targeting these metabolic pathways to treat IBD.

项目摘要 这项研究提案的目的是确定多胺在调节肠道固有淋巴系统中的作用。 细胞动态平衡。先天性淋巴样细胞(ILC)在粘膜屏障完整性和抵抗肺炎中起着关键作用。 病原性侮辱通过整合环境信号和快速分泌免疫调节 细胞因子。在肠道中，第3组ILC(ILC3)在抵抗病原菌定植方面起着至关重要的作用。 它们在促进上皮屏障功能，调节肠道髓系细胞， 并诱导粘膜内淋巴组织的形成，以协调肠道内环境的稳定。然而， ILC3调节失调推动肠道自身免疫，并与慢性炎症性肠炎有关 疾病(IBD)。尽管已知肠道淋巴细胞会按顺序进行大量的代谢适应 为了在组织中发挥作用，人们对细胞新陈代谢和各种 ILC3的功能。我们已经整合了单细胞RNA测序数据和非靶向代谢组学 肠道ILC鉴定ILC3中明显富含多胺和多胺代谢酶。 此外，我们的初步数据显示，多胺在支持ILC3增殖方面发挥了积极作用。 和功能。我们建议1)评估稳定状态下细胞内多胺对ILC3功能的影响 2)评估ILC3内源性多胺代谢在结肠炎临床前模型中的作用。我们 假设多胺正向调节ILC3功能，从而有助于 ILC3在结肠炎中的免疫病理作用 拟议的研究计划将确定多胺在增强其活性方面的ILC3固有贡献 并加重结肠炎。如果是这样的话，这些结果将进一步加深我们对代谢适应的理解 ILC3的作用以及针对这些代谢途径治疗IBD的潜在作用。