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Reciprocal regulation of microRNAs and cancer-associated signaling pathways

microRNA 和癌症相关信号通路的相互调节

基本信息

批准号：
8790432
负责人：
Scott Henry Olejniczak
金额：
$ 10.76万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-02-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8790432
关键词：
Affect Applications Grants Award Binding Bioenergetics Biogenesis Biology Cancer Biology Cell Line Cell Proliferation Cell physiology Cells Cellular biology Code Collaborations Complex Data Development Event Exhibits Extramural Activities Facility Accesses Funding Future Genetic Transcription Glucose Goals Growth Growth Factor Health Hexosamines Homeostasis In Vitro Individual Lesion Link Malignant - descriptor Malignant Neoplasms Mediating Memorial Sloan-Kettering Cancer Center Mentors Mentorship Metabolic Metabolic Pathway Metabolism MicroRNAs Microprocessor Mitogens Modeling Molecular Mus Normal Cell Nuclear Nutrient Oncogenes Oncogenic Organism Pathway interactions Phase Play Process Proliferating Proteins Publishing RNA RNA-Induced Silencing Complex Regulation Repression Research Resources Role Scientist Signal Pathway Signal Transduction Small RNA Stimulation of Cell Proliferation Stimulus T-Lymphocyte Techniques Testing Training Transcript Translations Tumor Suppressor Proteins United States National Academy of Sciences Universities Untranslated RNA anticancer research base cancer cell cancer type career cell growth cell growth regulation cytokine design glucose metabolism human FRAP1 protein insight mRNA Expression medical schools meetings member novel professional atmosphere receptor scaffold stem targeted cancer therapy therapeutic target

项目摘要

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.

描述(申请人提供)：这个K99/R00独立之路奖的最终目标是促进向独立癌症研究科学家职业生涯的过渡。这一目标将通过提供继续癌症生物学培训的机会来实现，获得各种新技术方面的专业知识，并产生一系列数据来指导未来的研究和申请外部资金。围绕这项提案的指导阶段的研究将在纪念斯隆-凯特琳癌症中心(MSKCC)的克雷格·B·汤普森博士的指导下进行。汤普森博士目前是MSKCC的总裁兼首席执行官、美国国家科学院院士和癌症生物学方面的领先专家。MSKCC拥有高度协作的氛围、最先进的设施以及访问威尔·康奈尔医学院和洛克菲勒大学的资源。过多的可用资源和合作机会将允许在完成下文概述的研究的同时成长为一名科学家。细胞的生长和增殖是高度协调的过程，受到有丝分裂信号的刺激，并受到可用的营养物质的推动。广义的有丝分裂信号来源于生长因子、细胞因子等对受体的刺激，或者是癌基因下游信号通路的异常激活，或者是肿瘤抑制因子的缺失。MicroRNA是一种小的非编码RNA，它调节基本的细胞过程，包括与癌症相关的有丝分裂信号。在最早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所必需的蛋白质，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microRNA的功能，提供了另一个联系，可能是通过促进RNA诱导沉默复合体(RISC)的组装，RISC是microRNA活动所需的蛋白质-RNA复合体。这些研究以及这项赠款申请中包含的初步数据表明，促进细胞生长和增殖的信号增强了microRNA的生物发生和功能。所提出的研究的主要目标是：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激活所需的因子；3)确定在静止细胞中高表达的microRNAs激活所影响的信号和代谢途径。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激活的潜在调控机制。其他研究将检验在静止细胞中高表达的microRNAs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提供一个新的框架，在其中将评估microRNA和癌症生物学的相互关系。