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依赖于信使RNA的命运-前mRNA如何剪接，mRNA如何以及何时翻译，以及最终何时降解。这些步骤的缺陷可能导致从遗传性疾病到癌症的疾病。由于它们作为RNA聚合物的性质，前mRNA和mRNA可能含有充当mRNA丰度和蛋白质合成的调节剂的二级和三级结构元件。尽管mRNA调控在生物学中具有核心重要性，但还没有系统水平的研究前mRNA和mRNA结构如何控制活细胞中的mRNA命运。 RNA系统生物学中心将使用新的方法来建立一个基本的基础，用于理解和预测由于嵌入前mRNA和mRNA序列中的RNA结构对mRNA命运的控制。该中心将联合收割机结合新的体内化学探测方法和细胞物理环境的控制，以实现以下具体目标： 1)确定前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的mRNA结构，以响应细胞的 物理环境。 3)Map RNA structural regulation of miRNA-mediated turnover. 最终，该中心的目标是开发前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潜在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.