Post-Transcriptional Regulation of Polycistronic MicroRNAs in Mammalian Cells

描述（由申请人提供）：Dr. Neilson是一名训练有素的发育免疫学家/小鼠遗传学家，他在菲利普A.夏普的实验室在麻省理工学院癌症研究中心，以获得更深入的了解短RNA生物学，以及成为在体外实验方法的简易。尼尔森博士的目标是在一家顶级研究机构领导一个学术实验室。 在获奖期间的指导阶段，尼尔森博士的目标是加强他对生物化学和生物信息学领域的接触。后一领域的培训尤其日益重要。在建议的指导阶段，Neilson博士将产生具有miR-92-1基因座的条件等位基因的小鼠。他还将启动致癌miR-17-92簇的生物化学表征，如提案中所述。夏普博士指导这种实验模式的能力是无与伦比的。同时，Neilson博士将参加学术和非学术课程，以精通编程和生物信息学方法，并教授短RNA和免疫学的高级本科课程。麻省理工学院和癌症研究中心拥有与这些目的相关的杰出核心设施和学术资源。 一旦指导阶段完成，Neilson博士和他的学员将继续对本文提出的小鼠突变体进行表征。Neilson博士新获得的生物化学和生物信息学技能将与他现有的哺乳动物发育和免疫学知识并行使用，以表征miR-92-1在表型，生物化学和基因组水平上破坏的后果。将检查在指导阶段期间进行的生化实验背景下miR-92-1破坏的后果。 通过一类称为miRNAs的新基因进行基因调控的发现从根本上改变了细胞如何控制基因表达的科学观点。这些基因中有几个与癌症有关。详细了解miRNAs如何工作以及它们本身是如何被控制的，将有助于更全面地理解哺乳动物生物学，同时能够更有效地利用产生这些基因用于治疗目的（RNAi）的途径。

DESCRIPTION (provided by applicant): Dr. Neilson is a trained developmental immunologist/mouse geneticist who has used the first portion of his postdoctoral fellowship in Phillip A. Sharp's lab at the the MIT Center for Cancer Research to gain a deeper understanding of short RNA biology, as well as to become facile with in vitro experimental approaches. Dr. Neilson's objective is to head an academic laboratory at a top research institution. During the mentored phase of the award period, Dr. Neilson aims to strengthen his exposure to the fields of biochemistry and bioinformatics. Training in the latter field in particular is increasingly important. During the mentored phase of the proposal, Dr. Neilson will generate mice with conditional alleles of the miR-92-1 locus. He will also initiate a biochemical characterization of the oncogenic miR-17-92 cluster as outlined in the proposal. Dr. Sharp's ability to mentor this mode of experimentation is unparalleled. Simultaneously, Dr. Neilson will take academic and non-academic courses to become fluent in programming and bioinformatic approaches, and teach an advanced undergraduate course in short RNAs and immunology. MIT and the Center for Cancer research have outstanding core facilities and academic resources relevant to these purposes. Once the mentored phase has been completed, Dr. Neilson and his trainees will continue the characterization of the mouse mutants proposed herein. Dr. Neilson's newly acquired biochemical and bioinformatic skill sets will be used in parallel with his existing knowledge of mammalian development and immunology to characterize the consequences of miR-92-1 disruption at the phenotypic, biochemical, and genomic levels. The consequences of miR-92-1 disruption in the context of the biochemical experiments performed during the mentored phase will be examined. The discovery of gene regulation by a new class of genes termed miRNAs has fundamentally changed the scientific view of how cells control gene expression. Several of these genes have been implicated in cancer. A detailed understanding how miRNAs work and how they themselves are controlled will allow a fuller comprehension of mammalian biology, at the same time enabling more effective exploitation of the pathway giving rise to these genes for therapeutic purposes (RNAi).