MicroRNA Function in the Immune System

描述（由申请人提供）：很明显，微小RNA（miRs）是一类小型非编码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，与转录因子偶联以提供精确的控制。该提案的重点是了解两种特定miR-146 a和miR-125 b在协调免疫中的作用，重点是了解为什么这些miR的缺失或过度产生会导致白血病。这项拟议研究的广泛目标是确定miR-146 a和miR-125 b协调血细胞形成，免疫功能和癌症发生的细胞和分子机制。 以前，我们产生了miR-146 a-/-小鼠，发现它们的造血干细胞耗尽，并发展出慢性炎症，骨髓细胞过度产生，导致明显的骨髓性白血病。我们发现，另一种细胞类型，淋巴细胞，对miR-146 a-/-小鼠骨髓增生性疾病和造血干细胞异常的发展有重要作用。我们现在将发现什么类型的淋巴细胞对这个过程很重要。我们还将确定由淋巴细胞产生的促炎细胞因子导致这些疾病和白血病诱导中涉及的分子途径。此外，我们将测试多个miRNAs协同作用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-146 a和miR-155之间的协同性，以及miR-146 a和miR-125 b。 除miR-146 a外，我们先前发现miR-125 B是通过增强巨噬细胞功能、抑制B细胞发育和损害T细胞功能的免疫效应物。与miR-146 a相反，miR-125 b的组成型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性白血病。随后，B细胞癌也在miR-125 B过表达小鼠中发生，可能是通过这些细胞内发生继发性遗传突变。在我们提出的研究中，我们将确定miR-125 B抑制B细胞发育和损害T细胞功能的细胞和分子机制。我们还将鉴定miR-125 b诱导的白血病细胞中的遗传癌症“驱动”突变和失调的信号通路，并确定这些异常中的哪一种诱导肿瘤。 在接下来的五年里，我们希望通过关注miR-146 a和miR-125 b来产生一些调节免疫细胞发育和功能的原理。更好地理解miRNAs对免疫系统的控制将为治疗免疫疾病和癌症开辟新的治疗途径。miR-146 a和miR-125 b的表达在人类白血病中经常失调，将我们的研究与公共卫生需求直接联系起来。

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.