Brain Enriched MicroRNA 128a and 9/9+: Impact on medulloblastoma pathogenesis

描述(申请人提供)：脑瘤是15岁以下儿童癌症死亡的主要原因。髓母细胞瘤是儿童最常见的恶性脑肿瘤，预后较差，与治疗相关的发病率较高。我们的目的是了解脑丰富的microRNAs在髓母细胞瘤发病机制中的作用。MicroRNAs是一种小的非编码RNA，通过抑制靶基因的翻译或降解mRNA来调节细胞的动态平衡。MicroRNAs可以作为肿瘤抑制基因或癌基因。利用miRNA微阵列分析，我们观察到与正常小脑相比，髓母细胞瘤中microRNAs的差异调节。我们建议研究三个特定的脑丰富的microRNAs，128a，9和9*，在髓母细胞瘤中的作用，特别是关于它们对小脑干细胞和髓母细胞瘤细胞增殖的影响。在特定的目标1中，我们将检验我们的假设，即microRNA128a和9/9*将抑制髓母细胞瘤细胞的增殖并促进分化。在此背景下，我们将确定并验证髓母细胞瘤中microRNA 128a的潜在靶点(目标2)。根据初步分析，我们假设microRNA128a靶向细胞周期调控因子BMI1。髓母细胞瘤可能源于小脑干细胞。在特定的目标3中，我们建议验证我们的假设，即microRNAs 128a和9/9*将在体内减弱小脑神经干细胞的致癌转化。K08培训基金的长期计划是让PI(Vibhakar医生)开发分子生物学工具和活体模型在儿科脑肿瘤应用方面的专业知识。培训期间将加强PI的教学和实践经验。在培训结束时，Vibhakar博士将成为一名独立的临床医生兼科学家，为推动儿科神经肿瘤学的治疗做出贡献。与公众健康相关：正常基因表达控制的改变与癌症有关。最近，microRNAs已经成为控制正常和恶性组织中基因表达的一个重要机制。人们对这些分子如何在髓母细胞瘤形成中发挥作用以及它们调节哪些基因知之甚少。这项研究将有助于了解它们在这种破坏性的儿童脑瘤中的作用，并可能在未来加强诊断和治疗。

DESCRIPTION (provided by applicant): Brain tumors are the leading cause of death from cancer in children under the age of 15 years. Medulloblastoma is the most common malignant brain tumor of childhood with poor outcomes and significant therapy related morbidity. Our objective is to understand the role of brain enriched microRNAs in medulloblastoma pathogenesis. MicroRNAs are small non-coding RNAs that regulate cell homeostasis by inhibiting translation or degrading mRNA of target genes. MicroRNAs can act as tumor supressor genes or oncogenes. Using miRNA microarray analysis we observed differential regulation of microRNAs in medulloblastoma compared to normal cerebellum. We propose to investigate the role of three specific brain enriched microRNAs, 128a, 9 and 9*, in medulloblastoma, particularly with respect to their impact on cerebellar stem cell and medulloblastoma cell proliferation. In Specific Aim 1, we will test our hypothsis that microRNA 128a and 9/9* will inhibit proliferation of medulloblastoma cells and potentiate differentiation. In this context we will identify and validate the potential targets of microRNA 128a in medulloblastoma (Aim 2). Based on preliminary analysis we hypothesize that microRNA 128a targets cell cycle regulator BMI1. Medulloblastoma can arise from cerebellar stem cells. In Specific Aim 3, we propose to test our hypothesis that microRNAs 128a and 9/9* will attenuate the oncogenic transformation of cerebellar neural stem cells in vivo. The long-term plan for this K08 training grant is for the PI (Dr. Vibhakar) to develop expertise in the application of molecular biology tools and in vivo models to pediatric brain tumors. The training period will enhance the didactic and practical experience of the PI. By the end of the training period Dr. Vibhakar will be poised as an independent clinician-scientist to contribute to advancing therapy in pediatric neurooncology. Relevance to public health: Alterations in the control of normal gene expression is associated with cancer. MicroRNAs have recently emerged as a significant mechanism in the control of gene expression in normal and malignant tissues. Little is known about how these molecules function in medulloblastoma formation and what genes they regulate. This study will help to understand their role in this devastating brain tumor of children and may enhance diagnosis and therapy in the future.