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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.

这个K99/R 00独立之路奖的最终目标是促进过渡到职业生涯作为一个独立的癌症研究科学家。这一目标将通过提供继续癌症生物学培训的机会来实现，获得各种新技术的专业知识，并生成一系列数据，这些数据将指导未来的研究和申请校外资助。包含本提案指导阶段的研究将在克雷格B博士的指导下进行。纪念斯隆-凯特琳癌症中心（MSKCC）。汤普森博士目前是MSKCC的总裁兼首席执行官，是美国国家科学院院士，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。大量的资源和合作机会将允许作为一个科学家的成长，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并由可用营养素提供燃料的高度协调的过程。广义上，促有丝分裂信号由生长因子、细胞因子等的受体刺激或癌基因下游的信号传导途径的异常激活或肿瘤抑制因子的缺失引起。microRNA是小的非编码RNA，其调节基本细胞过程，包括癌症相关的促有丝分裂信号传导。在癌症相关信号和microRNA之间的第一个观察到的联系是我们发现Ars 2，一个大的microRNA子集的表达所必需的蛋白质，是由促有丝分裂信号调节。最近，我们通过证明促有丝分裂和代谢信号增强microRNA功能提供了另一个联系，可能是通过促进RNA诱导沉默复合物（RISC）的组装，这是一种microRNA活性所需的蛋白质-RNA复合物。这些研究，沿着在这个拨款申请中包含的初步数据，表明microRNA的生物发生和功能是由促进细胞生长和增殖的信号增强的。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; 3）确定受在静止细胞中高度表达的microRNA活化影响的信号传导和代谢途径。为了实现这些目标，将进行正常细胞和癌细胞的体外操作，以阐明核microRNA生物合成，RISC组装和microRNA激活的调节机制。其他研究将检查在静止细胞中高度表达的microRNA调节癌症相关信号传导和细胞代谢的能力。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，在这个框架中，microRNA和癌症生物学的相互关系将得到评估。