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microRNAs and NKT cell development and function

microRNA 和 NKT 细胞的发育和功能

基本信息

批准号：
9241970
负责人：
QING-SHENG MI
金额：
$ 37.42万
依托单位：
HENRY FORD HEALTH SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-10 至 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9241970
关键词：
Antigens Autoimmune Diseases Autoimmunity Biogenesis Biological Biological Process Biology Cell Count Cell Maturation Cell Therapy Cell physiology Code Communicable Diseases Cytotoxic T-Lymphocytes Data Development Disease Down-Regulation Enzymes Gene Expression Gene Targeting Genes Goals Hematopoiesis Homeostasis Immune response Immunologics Impairment Infection Interruption Intervention Investigation Knock-in Mouse Knock-out Lead Link Lipids MHC Class I Genes Malignant Neoplasms Messenger RNA MicroRNAs Molecular Mus Mutant Strains Mice Outcome Pathway interactions Population Procedures Proteins Regulation Reporting Research Role Signal Pathway T-Cell Development T-Lymphocyte T-Lymphocyte Subsets Tamoxifen Testing Thymus Gland Untranslated RNA Up-Regulation anergy base cytokine experience gain of function insight mouse model protein expression public health relevance

项目摘要

DESCRIPTION (provided by applicant): Natural killer T (NKT) cells are an evolutionarily conserved subset of T cells that are developmentally and functionally distinct from conventional T cells. The ability to quickly secrete large quantities of a variety of cytokines upon activation enables NKT cells to be potent regulators of diverse immune responses. The deficiencies in NKT cell number and function have been linked to the development of many diseases. However, a significant gap remains in our understanding of how the development and function of NKT cells are precisely regulated. MicroRNAs (miRNAs), a recently discovered class of evolutionarily conserved small non-coding RNAs, negatively regulate the expression of protein-coding genes and thereby control essential biological functions and contribute to the development of many diseases. We were the first to report that the deletion of Dicer (a key enzyme for miRNA biogenesis) during hematopoiesis results in a significantly reduced NKT cell number and impaired NKT cell maturation and function, without alternating conventional T cell development in the thymus, suggesting that miRNAs are required for NKT cells. Our long-term goal is to understand how miRNAs regulate NKT cell development and function. While more than 1000 experimentally reported miRNAs, very few specific miRNAs are linked to NKT cells so far. Our objective here is to define specific miRNAs and their targets that regulate NKT cell development and function. Using miRNA arrays, we recently identified dynamic expression of miRNAs, including miR-155, and miR-17-92 cluster, during NKT cell development and activation. These findings plus our recent other reports lead to our central hypothesis that the dynamically expressed miRNAs serve as critical regulators controlling NKT cell development and function through fine-tuning specific target genes. Here we will further test this hypothesis t investigate how dynamic expression of miR-155 and miR-17-92 regulate NKT cell development and function using specific miRNA mutant mice with the gain or loss of miRNA function. The results from proposed studies may not only illuminate the new immunological and molecular mechanisms underlying NKT cell development, but may also facilitate the development of new and more efficient intervention strategies for autoimmune diseases, infection, and cancer based on the NKT cell therapy.

描述（由申请人提供）：自然杀伤T（NKT）细胞是一种进化上保守的T细胞亚群，在发育和功能上与常规T细胞不同。在活化后快速分泌大量多种细胞因子的能力使NKT细胞成为多种免疫应答的有效调节剂。NKT细胞数量和功能的缺陷与许多疾病的发展有关。然而，我们对NKT细胞的发育和功能如何精确调控的理解仍然存在重大差距。microRNAs（miRNAs）是近年来发现的一类进化上保守的非编码小RNA，通过负调控蛋白质编码基因的表达，从而控制重要的生物学功能，并与多种疾病的发生发展密切相关。我们是第一个报道造血过程中Dicer（miRNA生物合成的关键酶）的缺失导致NKT细胞数量显著减少，NKT细胞成熟和功能受损，而不会改变胸腺中的常规T细胞发育，这表明miRNA是NKT细胞所需的。我们的长期目标是了解miRNAs如何调节NKT细胞的发育和功能。虽然有超过1000种实验报道的miRNA，但到目前为止，很少有特定的miRNA与NKT细胞相关。我们的目标是确定特定的miRNAs及其调控NKT细胞发育和功能的靶点。利用miRNA阵列，我们最近确定了在NKT细胞发育和活化过程中miRNA的动态表达，包括miR-155和miR-17-92簇。这些发现加上我们最近的其他报告导致我们的中心假设，即动态表达的miRNAs通过微调特定的靶基因作为控制NKT细胞发育和功能的关键调节因子。在此，我们将进一步验证这一假设，以研究miR-155和miR-17-92的动态表达如何调节NKT细胞的发育和功能，使用特定的miRNA突变小鼠与miRNA功能的获得或丧失。从拟议的研究结果可能不仅阐明了新的免疫和分子机制的NKT细胞的发展，但也可能促进新的和更有效的干预策略的发展，自身免疫性疾病，感染和癌症的基础上NKT细胞治疗。