Center for RNA Systems Biology

描述（由申请人提供）： 人类生物学取决于人类基因组的表达方式。细胞中的蛋白质水平取决于信使 RNA 的命运——前 mRNA 如何剪接、mRNA 如何以及何时翻译，以及最终 mRNA 何时被降解。这些步骤的缺陷可能导致从遗传性疾病到癌症等疾病。就其 RNA 聚合物的性质而言，前 mRNA 和 mRNA 可能含有二级和三级结构元件，充当 mRNA 丰度和蛋白质合成的调节剂。尽管 mRNA 调控在生物学中具有核心重要性，但目前还没有关于前 mRNA 和 mRNA 结构如何控制活细胞中 mRNA 命运的系统级研究。 RNA 系统生物学中心将使用新方法为理解和预测由于嵌入前 mRNA 和 mRNA 序列中的 RNA 结构而对 mRNA 命运的控制奠定基础。该中心将把新的体内化学探测方法与细胞物理环境的控制相结合，以实现以下具体目标： 1) 确定前体mRNA中RNA结构在控制选择性剪接中的作用及其与人类遗传变异的关系。 2) 定义控制翻译起始和蛋白质合成以响应细胞的 mRNA 结构 物理环境。 3) 绘制 miRNA 介导的更新的 RNA 结构调控图。 该中心的最终目标是绘制前 mRNA 或 mRNA 序列中 RNA 结构的位置与 mRNA 命运之间的关系图。这些图谱将为人类生物学以及基因型变异和人类疾病的机制提供许多新的见解。

DESCRIPTION (provided by applicant): Human biology depends on the way the human genome is expressed. Protein levels in cells rely on the fate of messenger RNA-how pre-mRNAs are spliced, how and when mRNAs are translated, and finally when mRNAs are degraded. Defects in these steps can lead to diseases ranging from inherited disorders to cancer. By their nature as RNA polymers, pre-mRNAs and mRNAs may contain secondary and tertiary structural elements that serve as regulators of mRNA abundance and protein synthesis. Despite the central importance of mRNA regulation in biology, there has not been a systems-level study of how pre-mRNA and mRNA structure controls mRNA fate in living cells. The Center for RNA Systems Biology will use new methods to establish a fundamental basis for understanding and predicting the control of mRNA fate due to RNA structure embedded in pre-mRNA and mRNA sequences. The Center will combine new in vivo chemical probing methods with control of the physical environment of cells to address the following Specific Aims: 1) Determine the roles of RNA structure in pre-mRNAs in controlling alternative splicing and their Relationship to human genetic variation. 2) Define mRNA structures that control translation initiation and protein synthesis in response to a cell's physical environment. 3) Map RNA structural regulation of miRNA-mediated turnover. Ultimately the goal of the Center is to develop maps of relationships between the placement of RNA structure in pre-mRNA or mRNA sequences and mRNA fate. These maps will provide many new insights into human biology and the mechanisms underlying genotypic variation and human disease.