Interaction of TCL1 with a novel exoribonuclease

项目概述：该提案描述了一个为期3年的项目，旨在培养候选人成为肿瘤生物学的独立研究者。除了在匹兹堡大学完成分子生物学博士学位外，候选人还完成了解剖病理学的住院医师培训，肝脏和胃肠病理学的一年奖学金，并在加州大学洛杉矶分校实习了近三年的肝脏和胃肠病理学。在此期间，他在Michael Teitell博士的实验室从事博士后基础研究，研究致癌基因TCL1的调控及其在癌变中的作用。该计划将允许候选人在TCL1范围之外发展一个独立的研究计划。该研究将重点关注新发现的线粒体外核糖核酸酶PNPase在tcl1介导的恶性转化中所起的作用。Teitell实验室最近的工作帮助表征了一种新的TCL1转基因小鼠模型，该模型从生发中心b细胞发展出不同类型的成熟b细胞恶性肿瘤。该模型显示一种重要的增殖和细胞存活蛋白激酶AKT的激活增加，突出了tcl1介导的肿瘤形成的潜在机制。最近，候选人发现了第三种蛋白质，称为多核苷酸磷酸化酶（PNPase），直接结合TCL1。拟开展的实验将包括确定PNPase在TCL1/AKT介导的转化信号通路中的作用，以及确定PNPase本身与TCL1相关的独特生物学特性。这将提供一个坚实的，独立的工作基础，为候选人的功能作为一个研究人员。具体目的包括：1)确定PNPase在TCL1/AKT复合物形成和AKT活化中的作用；2)确定TCL1/PNPase复合物形成的影响；3)确定TCL1/PNPase对基因调控的影响。相关性：癌症发展的方式之一是通过细胞内通讯系统成分的水平和活动的变化，这决定了细胞是生长、停止生长还是死亡。这项研究将有助于理解这些细胞成分之一TCL1在与新发现的信号成分PNPase相互作用中向细胞发出癌变信号的机制。

DESCRIPTION (provided by applicant): Project summary: This proposal describes a 3 year program for the development of the candidate as an independent investigator in Tumor Biology. In addition to completing a Ph.D. in Molecular Biology at the University of Pittsburgh, the candidate has completed residency training in Anatomic Pathology, a year-long fellowship in Liver and Gastrointestinal Pathology, and has practiced Liver and Gastrointestinal Pathology for almost three years at the University of California at Los Angeles. During this time he has engaged in postdoctoral basic research in the laboratory of Dr. Michael Teitell studying the regulation of the oncogene TCL1 and its role in carcinogenesis. This proposed program will allow the candidate to develop an independent research program beyond the scope of TCL1. The research will focus on the role that a newly identified mitochondrial exoribonuclease, PNPase, plays in TCL1-mediated malignant transformation. Recent work in the Teitell lab helped characterize a new TCL1 transgenic mouse model that develops distinct types of mature B-cell malignancies from germinal center B-cells. This model shows an increased activation of an essential proliferation and cell survival protein kinase, AKT, highlighting a potential mechanism in TCL1-mediated tumor formation. More recently, the candidate identified a third protein, termed polynucleotide phosphorylase (PNPase), that directly binds TCL1. The proposed experiments will involve determination of the role PNPase plays in the signaling pathway of TCL1/AKT mediated transformation as well as defining the unique biology of PNPase itself as it related to TCL1. This will provide a firm, separate foundation of work for the candidate to function as an researcher. The specific aims include: 1) Determining the role of PNPase in TCL1/AKT complex formation and AKT activation; 2) Determining the effects of TCL1/PNPase complex formation; and 3) Determining the effect of TCL1/PNPase on gene regulation. Relevance: One of the ways that cancer develops is through changes in levels and activity of the components of the communication system within a cell that determines whether it grows, stops growing, or dies. This study will allow for understanding the mechanism by which one of these cell components, TCL1, signals a cell to become cancerous in its interaction with a newly identified signaling component PNPase.