Metabolic roles for Lin28-let-7 miRNA pathway in sarcoma tumorigenesis

描述（由申请人提供）：MicroRNAs （miRNAs）控制发育和癌症中的蛋白质输出。let-7 miRNA家族成员通过负向调节癌基因的翻译而发挥肿瘤抑制作用。rna结合蛋白Lin28a和Lin28b阻断所有let-7成员的加工并促进肿瘤进展。小鼠中Lin28a过表达导致过度生长和代谢改变，包括葡萄糖摄取增加、胰岛素敏感性增加和线粒体基因表达降低。由于在癌症中观察到这种代谢状态，朱博士假设Lin28a的这些发育功能与癌症特别相关。事实上，LIN28A和LIN28B在人类肉瘤和细胞系中过度表达，并且LIN28A Tg小鼠产生一系列软组织肿瘤。朱博士将验证Lin28/let-7通路驱动肉瘤生长和代谢变化的假设。具体而言，本提案旨在：1。确定Lin28/let-7通路在肉瘤小鼠模型中的作用，2。剖析Lin28和let-7调节肉瘤和肌肉代谢的机制。确定Lin28， Igf2bp和Hmga基因家族之间的相互作用如何影响肉瘤的生长和代谢。在K08奖的支持下完成后，该项目将确定mirna及其调控因子如何影响代谢，并可能在广泛的肿瘤和代谢疾病中具有治疗意义。朱博士是丹娜-法伯癌症研究所（DFCI）的临床肿瘤学研究员，他提出的5年指导研究计划将在波士顿儿童医院（CHB）血液学/肿瘤学科George Daley博士的实验室进行。朱博士拥有胚胎学和干细胞生物学背景，他的长期职业目标是整合他的科学和临床专业知识，研究临床相关癌症模型的代谢和发育机制。在癌症建模和干细胞生物学领域的领导者Dr. Daley的指导下，Zhu博士开发了一个研究和培训平台，该平台将为他提供必要的智力技能和实验方法，以便在指导和独立环境中都具有生产力。为了实现这一目标，朱博士将利用Daley实验室的专业知识和资源，接受代谢和代谢组学分析方面的正式培训，与专家团队建立合作和咨询，并通过当地和国际会议获得相关知识。该计划将在CHB的血液学/肿瘤学部门进行，该部门为培训医生科学家提供了丰富而成熟的环境。

DESCRIPTION (provided by applicant): MicroRNAs (miRNAs) control protein output in development and cancer. The let-7 miRNA family members act as tumor suppressors by negatively regulating the translation of oncogenes. The RNA-binding proteins Lin28a and Lin28b block the processing of all let-7 members and promote tumor progression. Lin28a overexpression in mice leads to overgrowth and metabolic alterations, including increased glucose uptake, increased insulin sensitivity, and decreased mitochondrial gene expression. Since this metabolic state is observed in cancer, Dr. Zhu hypothesized that these developmental functions for Lin28a are especially relevant in cancer. Indeed, LIN28A and LIN28B are overexpressed in human sarcomas and cell lines, and the Lin28a Tg mice develop an array of soft-tissue tumors. Dr. Zhu will test the hypothesis that the Lin28/let-7 pathway drives growth and metabolic changes in sarcoma. Specifically, this proposal will aim to: 1. Define the role of the Lin28/let-7 pathway in this mouse model of sarcoma, 2. Dissect the mechanism by which Lin28 and let-7 regulate metabolism in sarcoma and muscle and 3. Determine how interactions between the Lin28, Igf2bp and Hmga gene families affect growth and metabolism in sarcoma. When completed under the auspices of a K08 award, this project will define how miRNAs and their regulators can influence metabolism, and could have therapeutic implications in a broad array of neoplastic and metabolic diseases. Dr. Zhu is a clinical oncology fellow at Dana-Farber Cancer Institute (DFCI) and his proposed 5-year mentored research plan will be performed in the laboratory of Dr. George Daley in the Division of Hematology/Oncology at Children's Hospital Boston (CHB). Dr. Zhu's background is in embryology and stem cell biology, and his long-term career goal is to integrate his scientific and clinical expertise to investigate metabolic and developmental mechanisms in clinically relevant cancer models. Under the mentorship of Dr. Daley, a leader in cancer modeling and stem cell biology, Dr. Zhu has developed a research and training platform that will equip him with the intellectual skills and experimental approaches necessary to be productive in both a mentored and independent setting. To accomplish this, Dr. Zhu will take advantage of the expertise and resources of the Daley Lab, obtain formal training in metabolism and metabolomic analysis, establish collaboration and consultation with a team of experts, and acquire a relevant fund of knowledge through local and international meetings. The plan will be carried out in the Division of Hematology/Oncology at CHB, a rich and proven environment for training physician-scientists.