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：
9015979
负责人：
Scott Henry Olejniczak
金额：
$ 24.9万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9015979
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 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 abstracting 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

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.

项目摘要/摘要该K99/R00独立奖的最终目标是促进过渡到作为独立癌症研究科学家的职业。这个目标将通过提供继续接受癌症生物学培训的机会，获得各种新型技术的专业知识以及生成一系列数据，这些数据将指导未来的研究和应用壁外资金应用。研究涵盖本提案的指导阶段将在Craig B.博士的指导下进行。汤普森在纪念斯隆 - 凯特林癌症中心（MSKCC）。汤普森博士目前是总裁 MSKCC的首席执行官，美国国家科学院的成员，癌症生物学领先的专家。 MSKCC具有高度协作的氛围，最先进的设施和访问两者的资源威尔·康奈尔医学院和洛克菲勒大学。大量资源与协作可用的机会将允许作为科学家成长，同时完成以下概述的研究。细胞生长和增殖是由有丝分裂信号刺激的高度协调过程，由可用的营养物质加油。广泛定义的有丝分裂信号是由生长刺激引起的因素，细胞因子等，或来自癌基因下游信号通路的异常激活或丧失肿瘤抑制剂。 microRNA是调节基本细胞过程的小型非编码RNA，包括与癌症相关的有丝分裂信号传导。在与癌症相关的第一个观察到的联系中信号传导和microRNA是我们的发现，ARS2是一种表达大量子集所需的蛋白质 microRNA，受丝分裂信号调节。最近，我们通过证明有丝分裂和代谢信号增强了microRNA功能，可能是通过促进RNA-的组装诱导沉默复合物（RISC），这是microRNA活性所需的蛋白质-RNA复合物。这些研究，以及本赠款应用程序中包含的初步数据，表明microRNA生物发生和功能通过促进细胞生长和增殖的信号增强。拟议研究的主要目标是 1）确定调节核microRNA生物发生的细胞信号传导和代谢途径2）定义因素刺激的RISC组装和microRNA激活所需的因素，3）确定由MicroRNA激活影响的信号传导和代谢途径高度表达在静止的细胞。为了实现这些目标，将进行正常和癌细胞的体外操纵阐明核microRNA生物发生，RISC组装和 microRNA激活。其他研究将检查高度表达的microRNA的能力静止的细胞调节癌症相关的信号传导和细胞代谢。成功完成提议实现这些目标的研究将提供一个新颖的框架，在其中相互关系将评估microRNA和癌症生物学。