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mRNAs是如何拼接的，mRNAs是如何以及何时翻译的，最后是mRNAs何时被降解。这些步骤的缺陷可能会导致从遗传性疾病到癌症的一系列疾病。由于它们作为RNA聚合物的性质，前mRNAs和mRNAs可能包含二级和三级结构元素，作为mRNA丰度和蛋白质合成的调节因素。尽管信使核糖核酸调控在生物学中具有核心的重要性，但还没有关于前信使核糖核酸和信使核糖核酸结构如何控制活细胞中信使核糖核酸命运的系统水平的研究。 RNA系统生物学中心将使用新的方法为理解和预测由于嵌入在前mRNA和mRNA序列中的RNA结构而控制mRNA命运奠定基本基础。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结合起来，以解决以下具体目标： 1)确定前mRNAs中的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信使核糖核酸结构 物理环境。 3)MAP RNA对miRNA介导的周转的结构调控。 该中心的最终目标是开发RNA结构在前信使核糖核酸或信使核糖核酸序列中的位置与信使核糖核酸命运之间的关系图。这些图谱将为人类生物学以及基因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.