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，治疗相关发病率高。我们的目的是了解脑富集的microrna在成神经管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mRNA的翻译或降解来调节细胞稳态。MicroRNAs可以作为肿瘤抑制基因或致癌基因。通过miRNA微阵列分析，我们观察到髓母细胞瘤与正常小脑中microrna的差异调控。我们建议研究三种特定的脑富集microrna， 128a， 9和9*在成神经管细胞瘤中的作用，特别是它们对小脑干细胞和成神经管细胞瘤细胞增殖的影响。在Specific Aim 1中，我们将验证我们的假设，即microRNA 128a和9/9*会抑制成神经管细胞瘤细胞的增殖并增强分化。在这种情况下，我们将确定并验证microRNA 128a在成神经管细胞瘤中的潜在靶标（目的2）。根据初步分析，我们假设microRNA 128a靶向细胞周期调节因子BMI1。髓母细胞瘤可起源于小脑干细胞。在Specific Aim 3中，我们提出在体内验证我们的假设，即microRNAs 128a和9/9*会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博士）在分子生物学工具和儿童脑肿瘤体内模型的应用方面发展专业知识。培训期间将提高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科学家，为儿科神经肿瘤学的治疗进步做出贡献。与公众健康相关：正常基因表达控制的改变与癌症有关。近年来，MicroRNAs已成为控制正常和恶性组织中基因表达的重要机制。对于这些分子在成神经管细胞瘤形成过程中的作用以及它们调控的基因，我们知之甚少。这项研究将有助于了解它们在这种毁灭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.