The Role of MicroRNAs in Human Hematopoietic Cell Differentiation

描述(申请人提供)：本申请概述了一个3年的职业发展计划，以确保首席研究员在血液病和恶性血液病领域获得研究独立性的长期目标。这项建议将允许首席研究人员将他过去在AML细胞信号和生物信息学方面的经验整合到一个研究项目中，研究microRNAs(MiRNAs)及其对造血细胞谱系特异性分化的潜在贡献。首席研究人员将在人类造血祖细胞培养方面获得必要的技术专长，将人类白血病细胞系分化模型中的发现转化为人类造血。这将在约瑟夫·贝尔蒂诺博士(CINJ临时主任)的指导下完成，他曾指导过当今许多肿瘤学领导者的职业生涯，他的实验室在人类造血方面也有类似的兴趣。此外，首席研究员将在CINJ癌症基因组和分子肿瘤学主任阿诺德·拉布森博士的指导下获得转录和染色质分析方面的专业知识。为了进一步确保这一项目的成功，罗杰·斯特里尔博士(主任，恶性血红素，CINJ)和埃里克·鲁宾博士(首席，研究治疗，CINJ)已被招募为该提案的咨询委员会成员。本研究将通过对转铁蛋白受体1(TFR-1；CD71)作为佛波酯诱导的miRNAs靶标的分子分析，重点研究miRNAs在造血细胞分化中的作用。负责miRNA谱系特异性表达和转录激活的调控电路将通过对TPA诱导的原型miRNA miR-320的分子研究来阐明。最后，我们将通过将TFR-1和假定的TFR-1靶向miRNA在血统承诺的人脐血培养中的表达联系起来，并研究强制的TFR-1靶向miRNA表达对人类原发造血干细胞命运的影响，将我们的观察转化为人类初级造血干细胞的模型系统。最后，我们认为，使用miRNAs靶向TFR-1可能代表了一种新的策略，以破坏增殖优势，这是大多数人类恶性肿瘤的标志，并具有潜在的治疗应用。

DESCRIPTION (provided by applicant): This application outlines a 3 year career development plan to insure the principal investigator's long-term goal of attaining research independence in the fields of hemtopoiesis and hematologic malignancies. This proposal will allow the principal investigator to integrate his past experience in AML cell signaling and bioinformatics to a research program studying microRNAs (miRNAs) and their potential contribution to hematopoietic cell lineage-specific differentiation. The principal investigator will acquire the necessary technical expertise in human hematopoietic progenitor cell culture to translate findings made in a human leukemia cell line model of differentiation to human hematopoiesis. This will be accomplished under the mentorship of Dr. Joseph Bertino (Interim Director, CINJ), who has guided the careers of many of today's leaders in oncology and whose laboratory shares similar interests in human hematopoiesis. In addition, the principal investigator will gain expertise in transcription and chromatin analysis under the direction of Dr. Arnold Rabson, Chief of Cancer Genomics and Molecular Oncology at CINJ. To further insure this project's success, Dr. Roger Strair (Director, Heme Malignancies, CINJ) and Dr. Eric Rubin (Chief, Investigational Therapeutics, CINJ) have been enlisted to serve on this proposal's Advisory Committee. This research proposal will focus on the role of miRNAs in hematopoietic cell differentiation through the molecular analysis of transferrin receptor 1 (TfR-1; CD71) as a target of phorbol ester-induced miRNAs. The regulatory circuit responsible for miRNA lineage-specific expression and transcriptional activation will be elucidated by molecular studies of a prototypic TPA-induced miRNA, miR-320. Finally, we will translate our observations to a model system of primary human hematopoiesis by correlating TfR-1 and putative TfR-1 - targeting miRNA expression in lineage-committed human cord blood cultures, and studying the effect of enforced TfR-1-targeting miRNA expression on human primary hematopoietic stem cell fate decisions. Finally, it is our belief that TfR-1 targeting using miRNAs may represent a novel strategy to undermine the proliferative advantage that is the hallmark of the majority of human malignancies and have potential therapeutic applications.