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

描述（由申请人提供）：脑肿瘤是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，预后差，治疗相关的发病率高。我们的目的是了解脑富集microRNAs在髓母细胞瘤发病机制中的作用。MicroRNA是一类小的非编码RNA，通过抑制靶基因的翻译或降解靶基因的mRNA来调节细胞内环境的稳定。microRNA可以作为肿瘤抑制基因或癌基因。利用微RNA芯片分析，我们观察到与正常小脑相比，髓母细胞瘤中microRNA的差异调节。我们建议研究三种特定的脑富集microRNA，128a，9和9 *，在髓母细胞瘤中的作用，特别是它们对小脑干细胞和髓母细胞瘤细胞增殖的影响。在具体目标1中，我们将测试我们的假设，即microRNA 128 a和9/9 * 将抑制髓母细胞瘤细胞的增殖并增强分化。在这种情况下，我们将确定和验证microRNA 128 a在髓母细胞瘤中的潜在靶点（Aim 2）。基于初步分析，我们假设microRNA 128 a靶向细胞周期调节因子BMI1。成神经管细胞瘤可以起源于小脑干细胞。在具体目标3中，我们提出测试我们的假设，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培训补助金的长期计划是PI（Vibhakar博士）开发分子生物学工具和体内模型应用于儿科脑肿瘤的专业知识。培训期间将加强PI的教学和实践经验。在培训期结束时，Vibhakar博士将成为一名独立的临床医生-科学家，为推进儿科神经肿瘤治疗做出贡献。与公共卫生的相关性：正常基因表达控制的改变与癌症有关。microRNA最近已成为控制正常和恶性组织中基因表达的重要机制。关于这些分子在髓母细胞瘤形成中如何发挥作用以及它们调节哪些基因，我们知之甚少。这项研究将有助于了解他们在这种破坏性的儿童脑肿瘤中的作用，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.