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

• 批准号: 8718739
• 负责人: Li-Fan Lu
• 金额: $ 37.65万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 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/8718739
• 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; 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; public health relevance; response; selective expression; transcription factor

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) 是一类短的调节性非编码 RNA，因其在器官发育、细胞分化、稳态和功能中的作用而闻名，最近已被证明在调节免疫反应中至关重要。我们之前已经展示了 miRNA 通路在控制调节性 T (Treg) 细胞稳态和功能中不可或缺的作用。在 Treg 细胞中高表达的 miRNA 中，miR-155 和 miR-146a 分别在维持正常 Treg 细胞稳态以及更重要的是调节其对 Th1 炎症的抑制功能中发挥着关键作用。尽管如此，由于携带缺乏 miRNA 的 Treg 细胞的小鼠疾病表型的复杂性和严重性不能完全归因于上述单个 miRNA 的丢失，因此需要进一步阐明控制 Treg 细胞生物学其他特征所必需的其他 miRNA。与上述 miR-155 和 miR-146a 一样，miR-23 簇被发现在 Treg 细胞中至少部分以 Foxp3 依赖性方式高度上调。此外，Treg细胞和Tcon细胞之间miR-23簇的表达差异在激活后变得更大，因为它们在Treg细胞中进一步上调，而在Tcon细胞中下调。在这里，我们提出了一项多方面的研究，采用遗传、生化、免疫学方法和整体动物实验来全面检查 miR-23 簇介导的免疫调节的分子和细胞机制。首先，通过产生含有 miR-23 簇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 簇在生理和自身免疫环境中调节 Treg 细胞介导的免疫耐受中的作用。接下来，携带整个 miR-23a 簇以及簇内单个 miRNA 成员的条件性过表达转基因的小鼠的立即可用性将为系统地检查 miR-23 簇在各种环境中控制 T 细胞免疫中的作用提供机会。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鉴定由 miR-23 簇直接控制的靶标，探索 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础知识，并为开发操纵 Treg 细胞和效应 T 细胞功能的策略作为治疗人类免疫疾病的新方法提供进一步的见解。