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

基本信息

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
项目类别：
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

项目摘要

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细胞子集以及Inkt细胞细胞因子的产生和激活几乎完全未知。我们理解的差距代表了一个重要的挑战，特别是在考虑这些细胞对传染病的免疫学影响时。这长期目标是阐明Inkt细胞子集对感染的生理意义，如以及长期慢性炎症。该特定建议的总体目的是定义 Inkt细胞子集分化和激活中的microRNA（miRNA）。中心假设是独特的 miRNA调节特定Inkt细胞子集的分化。而且，我们假设某些miRNA 调节INKT激活，细胞因子产生及其抗炎反应。理由拟议的工作是通过了解miRNA如何调节Inkt细胞子集分化，激活和细胞因子的产生，我们可以开始理解这些Inkt细胞子集的相关性感染和慢性炎症。鉴于我们强大的初步数据，我们将通过以下具体目的：1）确定在inkt细胞子集分化和 2）确定特定miRNA在调节分化，细胞因子产生和体内inkt细胞的激活。在第一个目标下，miRNA作为inkt细胞向上和下调将评估分为特定子集。在第二个目标下，特定于Inkt细胞将采用条件方法以及种系缺乏方法来测试miR-155，miR-21的作用和miR-146a在这些细胞的子集分化和激活中。这种方法是创新的，因为它使用新型的小鼠菌株和基因表达分析来了解miRNA如何形状inkt细胞谱系分化和激活。有关miRNA和Inkt细胞的贡献的新研究可能性因此，可以实现免疫反应的子集。拟议的研究很重要，因为它将大大提高我们对Inkt细胞子集分化的调节和角色的理解在此过程发生时，由不同的miRNA播放。通过了解miRNA如何调节这一过程，我们有可能调节inkt细胞子集以获得更好的疾病结果。识别和分析 miRNA在NKT细胞子集分化，激活和细胞因子产生中的作用将告知我们对在治疗人类疾病中的inkt细胞。