MicroRNA regulation of Natural Killer T Cell differentiation and activation

MicroRNA 调节自然杀伤 T 细胞分化和激活

• 批准号: 9181052
• 负责人: Louise M. D'Cruz
• 金额: $ 19.09万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9181052
• 关键词: Ablation; Accounting; Address; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Cell Lineage; Cells; Cessation of life; Chronic; Communicable Diseases; Contracts; Cytokine Activation; Data; Development; Dicer Enzyme; Disease; Disease Outcome; Future; Gene Expression Profiling; Genetic; Glycolipids; Goals; Immune response; In Vitro; Infection; Inflammation; Inflammatory Response; Link; Lung; Maintenance; Malignant Neoplasms; Metabolism; MicroRNAs; Microarray Analysis; Molecular; Mouse Strains; Mus; Physiological; Play; Pneumococcal Infections; Process; Production; Proliferating; Regulation; Reporter; Research; Role; Shapes; Sorting - Cell Movement; Streptococcus pneumoniae; T cell differentiation; T-Cell Activation; T-Cell Development; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Thymus Gland; Up-Regulation; Work; alpha-galactosylceramide; base; cell type; cohort; cytokine; emergency service responder; follow-up; genetic approach; high reward; high risk; human disease; in vivo; innovation; killer T cell; mouse model; novel; recombinase; response; thymocyte

PROJECT SUMMARY How microRNAs regulate the newly described iNKT cell subsets as well as iNKT cell cytokine production and activation are almost completely unknown. This gap in our understanding represents an important challenge, especially when considering the immunological impact of these cells in response to infectious diseases. The long-term goal is to elucidate the physiological significance of iNKT cell subsets in response to infection, as well as long-term chronic inflammation. The overall objective of this specific proposal is to define the role of microRNAs (miRNAs) in iNKT cell subset differentiation and activation. The central hypothesis is that distinct miRNAs regulate differentiation of specific iNKT cell subsets. Moreover, we postulate that certain miRNAs regulate iNKT activation, cytokine production and their anti-inflammatory responses. The rationale for the proposed work is that by understanding how miRNAs regulate iNKT cell subset differentiation, activation and cytokine production, we can begin to understand the relevance of each of these iNKT cell subsets in response to infection and chronic inflammation. Given our strong preliminary data, we will test our hypotheses with the following specific aims: 1) Identify novel miRNAs upregulated during iNKT cell subset differentiation and 2) Determine the role of specific miRNAs in regulation of differentiation, cytokine production and activation of iNKT cells in vivo. Under the first aim, the miRNAs up- and down-regulated as iNKT cells differentiate into their specific subsets will be assessed. Under the second aim, an iNKT cell-specific conditional approach as well as germline-deficient approach will be taken to test the role of miR-155, miR-21 and miR-146a in subset differentiation and activation of these cells. This approach is innovative because it uses novel mouse strains and gene expression analysis to understand how miRNAs shape iNKT cell lineage differentiation and activation. New research possibilities regarding miRNAs and the contribution of iNKT cell subsets to the immune response will be attainable as a result. The proposed research is significant because it will substantially increase our understanding of how iNKT cell subset differentiation is regulated and the role played by distinct miRNAs as this process occurs. By understanding how miRNAs regulate this process, we will have the potential to modulate iNKT cell subsets for better disease outcome. Identification and analysis of the role of miRNAs in NKT cell subset differentiation, activation and cytokine production, will inform our use of iNKT cells in the treatment of human diseases.

项目摘要 microRNA如何调节新描述的iNKT细胞亚群以及iNKT细胞细胞因子的产生， 激活几乎完全未知。我们认识上的这一差距是一项重要挑战， 特别是当考虑到这些细胞对感染性疾病的免疫影响时。的 长期目标是阐明iNKT细胞亚群对感染应答的生理学意义， 以及长期慢性炎症。这一具体建议的总体目标是界定以下方面的作用： microRNAs（miRNAs）在iNKT细胞亚群分化和活化中的作用核心假设是， miRNA调节特定iNKT细胞亚群的分化。此外，我们假设某些miRNAs 调节iNKT活化、细胞因子产生及其抗炎反应。的理由 通过了解miRNAs如何调节iNKT细胞亚群的分化、激活和分化， 细胞因子的产生，我们可以开始了解这些iNKT细胞亚群中的每一个在应答中的相关性。 感染和慢性炎症。鉴于我们强大的初步数据，我们将使用 1）鉴定在iNKT细胞亚群分化过程中上调的新型miRNA， 2)确定特异性miRNAs在调节分化、细胞因子产生和 iNKT细胞在体内的活化。在第一个目标下，作为iNKT细胞， 将被区分为它们的特定子集。在第二个目标下，iNKT细胞特异性 将采用条件方法以及生殖系缺陷方法来测试miR-155、miR-21的作用 和miR-146 a在这些细胞的亚群分化和活化中的作用。这种方法是创新的，因为它 使用新的小鼠品系和基因表达分析来了解miRNAs如何塑造iNKT细胞谱系 分化和激活。关于miRNAs和iNKT细胞贡献的新研究可能性 结果将获得免疫应答的子集。这项研究意义重大，因为它 这将大大增加我们对iNKT细胞亚群分化是如何调节的理解， 在这个过程中由不同的miRNA发挥作用。通过了解miRNAs如何调节这一过程， 将具有调节iNKT细胞亚群以获得更好的疾病结果的潜力。查明和分析 miRNAs在NKT细胞亚群分化、活化和细胞因子产生中作用将为我们使用 iNKT细胞在人类疾病治疗中的应用