Characterizing tumor suppressive functions of microRNAs in B-cell neoplasia

描述(由申请人提供)：B细胞淋巴瘤是一种重要的临床问题，随着美国人口的老龄化，发病率和患病率正在上升。弥漫性大B细胞淋巴瘤是B细胞淋巴瘤中最常见的亚型，是一种由成熟的B细胞在抗原激活和分化为浆细胞的不同阶段引起的疾病。近年来，越来越明显的是，microRNAs(MiRNAs)，一种调节基因表达的小RNA分子，与肿瘤的发生和发育调节密切相关。该提案概述了一项为期5年的研究计划，以揭示两种肿瘤抑制基因miR-34a和miR-146a在B细胞淋巴瘤发病机制中的作用，了解它们在B细胞激活中的发育作用，并评估它们的作用机制。我们提出了以下假设：(1)miR-34a和miR-146a调节B细胞活化和浆细胞分化；(2)这两个miRNAs的异常调节参与了B细胞恶性肿瘤的发病；(3)它们在发育和恶性肿瘤中的作用机制与它们对几个关键靶点的调节有关。我们将结合基因定义的小鼠模型、逆转录病毒转导系统、骨髓移植、高通量方法、生物信息学和假设驱动的个体靶点研究来了解miRNAs在发育和肿瘤发生中的作用。这项建议具有显著的翻译性，未来的方向包括开发miRNAs的诊断和治疗应用。为成功实现这些目标，所有必要的方法、培训、资源、指导和人员都已到位。这些目标的完成有望极大地增加我们对关键生物学和病理过程的理解。也许最重要的是，它将为患有毁灭性的B细胞恶性疾病的患者提供一种非常有希望的治疗方法。

DESCRIPTION (provided by applicant): B-cell lymphoma is a significant clinical problem that is rising in incidence and prevalence as the American population ages. The most common subtype of B-cell lymphoma, diffuse large B-cell lymphoma, is a disease which arises from mature B-cells at various stages of antigenic activation and differentiation into plasma cells. Recently, it has become apparent that microRNAs (miRNAs), small RNA molecules that regulate gene expression, are intimately involved in oncogenesis and developmental regulation. This proposal outlines a 5-year research plan to unravel the role of two tumor- suppressor miRNAs, miR-34a and miR-146a, in B-cell lymphoma pathogenesis, to understand their developmental roles in B-cell activation and to evaluate their mechanism of action. We propose the following hypotheses: (i) miR-34a and miR-146a regulate B-cell activation and plasma cell differentiation (ii) Dysregulation of these two miRNAs contributes to the pathogenesis of B-cell malignancies and (iii) the mechanism of their action in both development and malignancy relates to their regulation of several critical targets. We will use a combination of genetically defined murine models, retroviral transduction systems, bone marrow transplantation, high-throughput approaches, bioinformatics, and hypothesis-driven investigation of individual targets to understand the role of miRNAs in development and oncogenesis. This proposal is eminently translational and future directions include the development of diagnostic and therapeutic applications of miRNAs. All of the necessary methodology, training, resources, mentorship and personnel are in place for the successful completion of these goals. The completion of these goals promises to significantly increase our understanding of critical biological and pathological processes. Perhaps most importantly, it will bring forward a highly promising approach to treatment of patients who suffer from devastating malignant diseases of B-cells.