MicroRNA Function in the Immune System

描述(由申请人提供)：很明显，microRNAs(MiRs)，一类小的非编码RNA，是细胞系统的重要调节因子。我们已经发现，某些MIR对免疫系统的发育和功能非常重要，与转录因子结合提供精确的控制。这项建议的重点是了解两个特定的miR，miR-146a和miR-125b在协调免疫中的作用，重点是了解为什么这些miR的缺失或过度生产会导致白血病。这项拟议研究的主要目标是确定miR-146a和miR-125b协调血细胞形成、免疫功能和癌症发生的细胞和分子机制。之前，我们培育了miR-146a-/-小鼠，发现它们会耗尽造血干细胞，并发展成慢性炎症，髓系细胞过度生产导致坦率的髓系白血病。我们发现，另一种细胞类型，淋巴细胞，在miR-146a-/-小鼠的髓系增殖性疾病和造血干细胞异常的发展中起重要作用。我们现在将发现什么类型的淋巴细胞对这个过程很重要。我们还将确定导致这些疾病的淋巴细胞产生的促炎细胞因子以及诱导白血病的分子途径。此外，我们将检验多个miRNAs协同作用以调节免疫细胞发育和功能的假设。在这方面，我们的重点将是miR-146a和miR-155以及miR-146a和miR-125b之间的协同性。除miR-146a外，我们先前还发现miR-125b通过增强巨噬细胞功能、抑制B细胞发育和损害T细胞功能而发挥免疫效应。与miR-146a不同，miR-125b的结构性过表达通过不需要淋巴细胞的细胞内在过程快速诱导侵袭性髓系白血病。后来，B细胞癌也在miR-125b过度表达的小鼠中发展，可能是通过在这些细胞内发生次级基因突变。在我们提出的研究中，我们将确定miR-125b抑制B细胞发育和损害T细胞功能的细胞和分子机制。我们还将在miR-125b诱导的白血病细胞中识别遗传癌的驱动因素突变和失调的信号通路，并确定这些异常中的哪一种会导致肿瘤。在接下来的五年里，我们希望通过专注于miR-146a和miR-125b来产生一些免疫细胞发育和功能调节的原理。更好地了解miRNAs对免疫系统的控制将可能为治疗免疫性疾病和癌症开辟新的治疗途径。MiR-146a和miR-125b在人类白血病中的表达经常是失调的，这直接将我们的研究与公共卫生需求联系在一起。

DESCRIPTION (provided by applicant): It has become apparent that microRNAs (miRs), a class of small non-coding RNAs, are important regulators of cellular systems. We have found that certain miRs are profoundly important to the development and function of the immune system, coupling with transcription factors to provide precise control. The focus of this proposal is on understanding the roles of two particular miRs, miR-146a and miR-125b, in orchestrating immunity, with an emphasis on understanding why either deletion or overproduction of these miRs causes leukemia. The broad goal of this proposed research is to determine the cellular and molecular mechanisms by which miR-146a and miR-125b orchestrate blood cell formation, immune function, and cancer occurrence. Previously, we generated miR-146a-/- mice and found that they become depleted of hematopoietic stem cells and develop chronic inflammation with an overproduction of myeloid cells leading to frank myeloid leukemia. We found that another cell type, lymphocytes, contribute importantly to the development of myeloid proliferative disease and hematopoietic stem cell abnormalities in miR-146a-/- mice. We will now discover what type of lymphocyte is important to this process. We will also identify the pro-inflammatory cytokines produced by the lymphocytes to cause these disorders and the molecular pathways involved in leukemia induction. Additionally, we will test the hypothesis that multiple miRNAs function cooperatively to regulate immune cell development and function. In this regard, our focus will be on the cooperativity between miR-146a and miR-155, as well as miR-146a and miR-125b. In addition to miR-146a, we previously found that miR-125b is an effector of immunity by augmenting macrophage function, inhibiting B cell development, and impairing T cell function. In contrast to miR-146a, constitutive over-expression of miR-125b rapidly induces aggressive myeloid leukemia through a cell intrinsic process not requiring lymphocytes. Later, B cell cancers also develop in miR-125b over-expressing mice, likely through the occurrence of secondary genetic mutations within these cells. In our proposed research, we will determine the cellular and molecular mechanisms by which miR-125b inhibits B cell development and impairs T cell function. We will also identify genetic cancer 'driver' mutations and dysregulated signal pathways in miR-125b-induced leukemic cells and determine which of these abnormalities induces tumors. Over the next five years, we hope to generate some principles of the regulation of immune cell development and functions by focusing on miR-146a and miR-125b. A better understanding of the control exerted by miRNAs on the immune system will potentially open up new therapeutic avenues for treating immunologic diseases and cancer. The expression of miR-146a and miR-125b is often dysregulated in human leukemia, linking our research directly to public health needs.