Functional Analysis of MicroRNAs in Lymphocyte Development and Immune Tolerance

描述(申请人提供)：microRNAs(MiRNAs)最近成为一类主要的反式因子，在mRNA水平上调节蛋白质编码基因的表达，从而控制包括细胞分化、增殖和凋亡在内的各种生物学过程。我们和其他研究小组的遗传学研究表明，miRNAs参与了淋巴细胞发育和功能的控制，以及自身免疫性疾病。然而，单个miRNAs在免疫系统中的具体功能在很大程度上仍不清楚。我们建议使用新开发的慢病毒miRNA表达文库、最近发表的miRNA海绵技术和一个独特的B细胞耐受小鼠模型来系统地评估miRNAs在B细胞发育和耐受中的功能。这一建议的主要目的是确定在B细胞发育和耐受中发挥重要作用的miRNAs，并通过这样做为未来深入研究单个miRNAs的特定功能和分子机制开辟新的途径。 公共卫生相关性：拟议研究的初步影响将是促进我们对特定miRNAs与淋巴细胞发育和免疫耐受之间关系的理解。从长远来看，我们在这些实验中发现的miRNAs本身可能是有价值的诊断标记和自身免疫性疾病、器官移植和癌症免疫治疗的可能靶点。此外，对这些miRNAs的靶标识别将导致发现成为治疗干预理想靶点的蛋白质编码基因。

DESCRIPTION (provided by applicant): MicroRNAs (miRNAs) have recently emerged as a major class of trans-factors that regulate expression of protein coding genes at the mRNA level, thereby controlling a diverse range of biological processes including cell differentiation, proliferation, and apoptosis. Genetic studies from us and other groups have demonstrated that miRNAs are involved in the control of lymphocyte development and function, as well as in autoimmune diseases. However, the specific functions of individual miRNAs in the immune system remain largely unknown. We propose to use a newly developed lentiviral miRNA expression library, the recently published miRNA sponge technology, and a unique mouse model of B cell tolerance to systematically assess the functions of miRNAs in B cell development and tolerance. The primary goal of this proposal is to identify miRNAs that play important roles in B cell development and tolerance and, by doing so, to open up new avenues for in-depth studies of specific functions and molecular mechanisms of individual miRNAs in the future. PUBLIC HEALTH RELEVANCE: The initial impact of the proposed research will be on advancing our understanding of the relationships between particular miRNAs and lymphocyte development and immune tolerance. In the long run, the miRNAs that we uncover during these experiments may themselves be valuable diagnostic markers and possible targets of therapeutics for autoimmune diseases, organ transplantation, and cancer immune therapy. Furthermore, target identification for these miRNAs will lead to the discovery of protein coding genes that make ideal targets for therapeutic interventions.