Reciprocal regulation of microRNAs and cancer-associated signaling pathways

项目摘要/摘要 这个K99/R00独立之路奖的最终目标是促进向 作为一名独立的癌症研究科学家。这一目标将通过提供 有机会继续接受癌症生物学方面的培训，获得各种新技术的专业知识，以及 产生大量数据，以指导未来的研究和申请外部资金。研究 将在克雷格·B博士的指导下进行这项提案的指导阶段。 汤普森在纪念斯隆-凯特琳癌症中心(MSKCC)。汤普森博士现任总统和 MSKCC首席执行官、美国国家科学院院士和癌症生物学领域的领先专家。 MSKCC拥有高度协作的氛围、最先进的设施和访问双方的资源 威尔康奈尔医学院和洛克菲勒大学。过多的资源和协作 在完成下面概述的研究的同时，现有的机会将允许作为一名科学家成长。 细胞生长和增殖是高度协调的过程，由有丝分裂信号和 以可获得的营养为燃料。广义的有丝分裂信号是由生长刺激的受体产生的。 因子、细胞因子等，或癌基因下游信号通路的异常激活或丢失 肿瘤抑制因子。MicroRNA是一种小的非编码RNA，调节基本的细胞过程， 包括癌症相关的有丝分裂信号。在最早观察到的癌症相关因素之间的联系中 信号和microRNAs是我们发现的Ars2，一种表达一大亚组基因所必需的蛋白质 MicroRNAs，受有丝分裂信号调控。最近，我们提供了一个额外的链接，通过演示 有丝分裂和代谢信号增强microRNA的功能，可能是通过促进RNA- 诱导沉默复合体(RISC)，是microRNA活动所必需的蛋白质-RNA复合体。这些研究， 连同这项拨款申请中包含的初步数据表明，microRNA的生物发生和功能 被促进细胞生长和增殖的信号所增强。拟议研究的主要目标是 1)确定调控核microRNA生物发生的细胞信号和代谢途径2) 确定丝裂原刺激的RISC组装和microRNA激活所需的因素，以及3)确定 高表达的microRNAs激活对信号和代谢途径的影响 静止的细胞。为了实现这些目标，将对正常细胞和癌细胞进行体外操作 为了阐明核microRNA生物发生、RISC组装和核microRNA生物发生的调控机制 MicroRNA的激活。更多的研究将检验在细胞中高度表达的microRNA的能力 静止细胞调节癌症相关信号和细胞新陈代谢。成功完成 为实现这些目标而提出的研究将提供一个新的框架，其中 将对microRNA和癌症生物学进行评估。

Project Summary/Abstract The ultimate goal of this K99/R00 Pathway to Independence Award is to facilitate the transition to a career as an independent cancer research scientist. This goal will be accomplished by providing the opportunity to continue training in cancer biology, acquire expertise in a variety of novel techniques, and generate a body of data that will guide future studies and applications for extramural funding. Research encompassing the mentored phase of this proposal will be conducted under the mentorship of Dr. Craig B. Thompson at Memorial Sloan-Kettering Cancer Center (MSKCC). Dr. Thompson is currently President and CEO of MSKCC, a member of the National Academy of Sciences and a leading expert in cancer biology. MSKCC has a highly collaborative atmosphere, state-of-the-art facilities and access to the resources of both Weill Cornell Medical College and The Rockefeller University. The plethora of resources and collaboration opportunities available will allow for growth as a scientist while completing the research outlined below. Cell growth and proliferation are highly coordinated processes stimulated by mitogenic signals and fueled by available nutrients. Broadly defined, mitogenic signals result from receptor stimulation by growth factors, cytokines, etc. or from aberrant activation of signaling pathways downstream of oncogenes or loss of tumor suppressors. MicroRNAs are small non-coding RNAs that regulate fundamental cellular processes, including cancer-associated mitogenic signaling. Among the first observed links between cancer-associated signaling and microRNAs was our discovery that Ars2, a protein necessary for expression of a large sub-set of microRNAs, is regulated by mitogenic signals. Recently we provided an additional link by demonstrating that mitogenic and metabolic signals enhance microRNA function, likely by promoting the assembly of the RNA- induced silencing complex (RISC), a protein-RNA complex required for microRNA activity. These studies, along with preliminary data contained in this grant application, suggest that microRNA biogenesis and function are enhanced by signals that promote cell growth and proliferation. The major goals of proposed research are 1) determining cellular signaling and metabolic pathways that regulate nuclear microRNA biogenesis 2) defining factors required for mitogen-stimulated RISC assembly and microRNA activation, and 3) determining the signaling and metabolic pathways affected by activation of microRNAs that are highly expressed in quiescent cells. To accomplish these goals, in vitro manipulation of normal and cancer cells will be performed to elucidate mechanisms underlying regulation of nuclear microRNA biogenesis, RISC assembly and microRNA activation. Additional studies will examine the ability of microRNAs that are highly expressed in quiescent cells to regulate cancer-associated signaling and cellular metabolism. Successful completion of research proposed to meet these goals will provide a novel framework in which the interrelationship of microRNA and cancer biology will be assessed.