Reciprocal regulation of microRNAs and cancer-associated signaling pathways

描述（由申请人提供）：K99/R00独立之路奖的最终目标是促进作为独立癌症研究科学家的职业过渡。这一目标将通过提供继续接受癌症生物学培训的机会，获得各种新技术的专业知识，并生成指导未来研究和校外资助应用的数据体来实现。包含该提案指导阶段的研究将在纪念斯隆-凯特琳癌症中心（MSKCC）的Craig B. Thompson博士的指导下进行。Thompson博士目前是MSKCC的总裁兼首席执行官，是美国国家科学院（National Academy of Sciences）的成员，也是癌症生物学的领先专家。MSKCC拥有高度协作的氛围，最先进的设施，并可获得威尔康奈尔医学院和洛克菲勒大学的资源。大量可用的资源和合作机会将允许科学家在完成以下研究的同时成长。细胞生长和增殖是一个高度协调的过程，由有丝分裂信号刺激，并由可用的营养物质推动。从广义上讲，有丝分裂信号是由生长因子、细胞因子等对受体的刺激或癌基因下游信号通路的异常激活或肿瘤抑制因子的缺失引起的。MicroRNAs是一种小的非编码rna，它调节基本的细胞过程，包括癌症相关的有丝分裂信号。在首次观察到的癌症相关信号和microRNAs之间的联系中，我们发现Ars2是一种表达大量microRNAs所需的蛋白质，受有丝分裂信号的调节。最近，我们通过证明有丝分裂和代谢信号增强了microRNA的功能，可能是通过促进RNA诱导沉默复合体（RISC）的组装，这是一种microRNA活性所需的蛋白质-RNA复合体，提供了额外的联系。这些研究以及本资助申请中包含的初步数据表明，促进细胞生长和增殖的信号可以增强microRNA的生物发生和功能。提出的研究的主要目标是：1)确定调节核microRNA生物发生的细胞信号传导和代谢途径；2)确定丝裂原刺激的RISC组装和microRNA激活所需的因子；3)确定受静态细胞中高表达的microRNA激活影响的信号传导和代谢途径。为了实现这些目标，将对正常细胞和癌细胞进行体外操作，以阐明核microRNA生物发生、RISC组装和microRNA激活的调控机制。进一步的研究将检验在静止细胞中高度表达的microrna调节癌症相关信号和细胞代谢的能力。为实现这些目标而提出的研究的成功完成将为评估microRNA与癌症生物学的相互关系提供一个新的框架。

DESCRIPTION (provided by applicant): 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.