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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：
8634982
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 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8634982
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 Critiques Data Development Event Exhibits Extramural Activities Facility Accesses Functional RNA 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 Writing anticancer research base cancer cell cancer therapy cancer type career cell growth cell growth regulation cytokine design glucose metabolism human FRAP1 protein insight mRNA Expression medical schools meetings member novel planetary Atmosphere public health relevance receptor scaffold stem 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.

项目总结/摘要这个K99/R 00独立之路奖的最终目标是促进过渡到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培训，获得各种新技术的专业知识，生成一个数据体，将指导未来的研究和申请校外资助。研究将在克雷格B博士的指导下进行本提案的指导阶段。纪念斯隆-凯特琳癌症中心（MSKCC）。汤普森博士目前是总统， MSKCC的首席执行官，美国国家科学院院士，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两者的资源威尔康奈尔医学院和洛克菲勒大学。过多的资源和协作现有的机会将允许成长为一个科学家，同时完成下面概述的研究。细胞生长和增殖是由促有丝分裂信号刺激的高度协调的过程，以可利用的营养为燃料。广义上讲，促有丝分裂信号是由生长刺激受体引起的因子、细胞因子等，或来自癌基因下游的信号传导途径的异常激活或癌基因的缺失。肿瘤抑制剂。microRNA是调节基本细胞过程的小的非编码RNA，包括癌症相关的促有丝分裂信号。在第一次观察到的癌症相关性之间的联系，我们发现Ars 2是一种表达一个大的信号转导子组所必需的蛋白， microRNAs受有丝分裂信号的调控。最近，我们通过演示提供了一个额外的链接，促有丝分裂和代谢信号增强microRNA的功能，可能是通过促进RNA的组装，诱导沉默复合物（RISC），是microRNA活性所需的蛋白质-RNA复合物。这些研究，沿着在这个资助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)确定调节核microRNA生物发生的细胞信号传导和代谢途径2）确定促分裂原刺激的RISC组装和microRNA活化所需的因子，以及3）确定受微RNA激活影响的信号传导和代谢途径，微RNA在细胞中高度表达，静止细胞为了实现这些目标，将进行正常细胞和癌细胞的体外操作阐明核microRNA生物合成、RISC组装和 microRNA激活。进一步的研究将检查在细胞中高度表达的microRNA的能力。静止细胞来调节癌症相关的信号传导和细胞代谢。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，将评估microRNA和癌症生物学。