Role of microRNAs in regulatory T cell-mediated immunological tolerance and T cel

microRNA在调节性T细胞介导的免疫耐受和T细胞中的作用

基本信息

批准号：
8912615
负责人：
Li-Fan Lu
金额：
$ 4.65万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8912615
关键词：
Alleles Animal Experimentation Asthma Autoimmune Process Autoimmunity Biochemical Biological Cell physiology Cells Cellular biology Complex Cues Development Effector Cell Ensure Equilibrium Exhibits Experimental Animal Model Family Functional RNA Genes Genetic Goals Health Homeostasis Host Defense Human Immune Immune System Diseases Immune response Immunity Individual Inflammation Knowledge Lead Mediating Mediator of activation protein Messenger RNA MicroRNAs Molecular Mus Organ Outcome Pathway interactions Phenotype Physiological Play Population Process Regulation Regulatory T-Lymphocyte Role Severities T cell differentiation T-Cell Activation T-Lymphocyte T-Lymphocyte Subsets Tissues Transgenes cellular development chemokine receptor cytokine disease phenotype human disease insight loss of function member microbial novel therapeutic intervention pathogen response selective expression transcription factor

项目摘要

DESCRIPTION (provided by applicant): Numerous microRNA (miRNA), a class of short regulatory non-coding RNAs known for their role in organ development, cellular differentiation, homeostasis, and function, have been recently demonstrated to be pivotal in regulating immune responses. We have previously shown an indispensable role of the miRNA pathway in controlling regulatory T (Treg) cell homeostasis and function. Among miRNAs highly expressed in Treg cells, miR-155 and miR-146a play pivotal roles in maintaining normal Treg cell homeostasis and more importantly regulating their suppressor function to Th1 inflammation, respectively. Nonetheless, because the complexity and the severity of the disease phenotypes in mice harboring Treg cells devoid of miRNA cannot be attributed entirely to the loss of aforementioned individual miRNAs, additional miRNAs essential for controlling other features of Treg cell biology require further elucidation. Like miR-155 and miR-146a described above, miR-23 clusters were found to be highly upregulated in Treg cells at least partially in a Foxp3 dependent manner. Moreover, the differences in the expression of miR-23 clusters between Treg cells and Tcon cells became even larger upon activation as they were further upregulated in Treg cells while downregulated in Tcon cells. Here, we propose a multifaceted study employing genetic, biochemical, immunological approaches and whole animal experimentation to comprehensively examine the molecular and cellular mechanisms underlying miR-23 cluster-mediated immune regulation. First, by generating mice harboring conditional alleles of miR-23 clusters, this loss-of-function approach will allow us to examine the role of miR-23 clusters in regulating Treg cell-mediated immunological tolerance in both physiological and autoimmune settings. Next, the immediate availability of mice harboring conditional over-expressing transgenes of the whole miR-23a cluster as well as individual miRNA member within the cluster will afford the opportunity to systematically examine the role of miR-23 cluster in controlling T cell immunity in various settings. Finally, we will explore the putative molecular mechanisms underlying miR-23 cluster-dependent immune regulation through identification of genes that are regulated in miR-23 cluster-dependent manner and through identification of targets that are directly controlled by miR-23 clusters. The proposed studies will greatly extend our fundamental knowledge of miRNA-mediated immune regulation and provide further insights into the development of strategies to manipulate Treg cell and effector T cell function as novel therapeutic approaches for treating human immunological diseases.

描述（由申请人提供）：许多microRNA（miRNA），这是一类以器官发育，细胞分化，稳态和功能而闻名的短调节性非编码RNA，最近已被证明是调节免疫反应的关键。以前，我们已经表现出miRNA途径在控制调节t（Treg）细胞稳态和功能中具有必不可少的作用。在Treg细胞中高度表达的miRNA中，miR-155和miR-146a在维持正常的Treg细胞稳态中起关键作用，更重要的是将其抑制功能调节至Th1炎症。尽管如此，由于藏有miRNA的Treg细胞中疾病表型的复杂性和严重程度不能完全归因于上述单个miRNA的丧失，因此需要进一步阐明Treg细胞生物学的其他特征对于控制Treg细胞生物学的其他特征必不可少的MiRNA。像上述miR-155和miR-146a一样，发现miR-23簇在Treg细胞中至少以FOXP3依赖性方式被高度上调。此外，在激活中，Treg细胞和TCON细胞之间miR-23簇的表达差异变得更大，因为它们在TCOR细胞中被下调，而在TCOR细胞中被下调。在这里，我们提出了一项采用遗传，生化，免疫学方法和整个动物实验的多面研究，以全面检查miR-23簇簇介导的免疫调节的分子和细胞机制。首先，通过产生具有miR-23簇有条件等位基因的小鼠，这种功能丧失方法将使我们能够检查miR-23簇在调节Treg细胞介导的免疫耐受性中在生理和自身免疫性环境中的作用。接下来，具有有条件过表达的整个miR-23A簇的有条件过表达的转基因的小鼠以及集群中的单个miRNA成员有机会系统地检查miR-23簇在各种环境中控制T细胞免疫中的作用。最后，我们将通过鉴定以miR-23簇依赖性方式调节的基因以及通过鉴定由miR-23簇直接控制的靶标，探讨miR-23簇依赖性免疫调节的假定分子机制。拟议的研究将极大地扩展我们对miRNA介导的免疫调节的基本知识，并进一步见识开发操纵Treg细胞的策略和效应T细胞功能，作为治疗人类免疫疾病的新型治疗方法。