Post-Transcriptional Regulation of Polycistronic MicroRNAs in Mammalian Cells

简介(申请人提供)：尼尔森博士是一名训练有素的发育免疫学家/小鼠遗传学家，他利用菲利普·A·夏普在麻省理工学院癌症研究中心的实验室获得的博士后奖学金的第一部分，对短RNA生物学有了更深入的了解，并熟悉了体外实验方法。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。 在获奖期的指导阶段，尼尔森博士的目标是加强他在生物化学和生物信息学领域的接触。后一领域的培训尤其重要。在该计划的指导阶段，尼尔森博士将培育出带有miR-92-1基因座条件性等位基因的小鼠。他还将启动该提案中概述的致癌miR-17-92簇的生化表征。夏普博士指导这种实验模式的能力是无与伦比的。与此同时，尼尔森博士将选修学术和非学术课程，以流利地掌握编程和生物信息学方法，并教授简短的RNA和免疫学方面的高级本科课程。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，尼尔森博士和他的受训人员将继续描述这里提出的小鼠突变的特征。Neilson博士新获得的生化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结合使用，以表征miR-92-1中断在表型、生化和基因组水平上的后果。在指导阶段进行的生化实验中，将检查miR-92-1中断的后果。 由一类名为miRNAs的新基因调控基因的发现，从根本上改变了细胞如何控制基因表达的科学观点。其中几个基因被认为与癌症有关。详细了解miRNAs是如何工作的以及它们本身是如何受到控制的，将使我们能够更全面地理解哺乳动物生物学，同时能够更有效地利用导致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).