MicroRNA Deregulation in JAK2V617F-positive Chronic Myeloid Neoplasms

JAK2V617F 阳性慢性髓系肿瘤中的 MicroRNA 失调

• 批准号: 8698317
• 负责人: Huichun Zhan
• 金额: --
• 依托单位: NORTHPORT VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8698317
• 关键词: Academic Medical Centers; Address; Affect; Age; Alleles; Androgens; Biochemistry; Biological Assay; Biology; Blood Cells; CD34 gene; Cell Line; Cell Proliferation; Cell physiology; Cells; Chronic; Clinical; Commit; Development; Diagnosis; Diagnostic tests; Disease; Down-Regulation; Erythrocytoses; Erythroid; Erythroid Progenitor Cells; Erythropoiesis; Fostering; Foundations; Genes; Healthcare Systems; Hematologic Neoplasms; Hematology; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Hemorrhagic Thrombocythemia; In Vitro; Internal Medicine; Investigation; JAK2 gene; Knowledge; Laboratories; Measures; Medical center; Mentors; Methods; Methylcellulose; MicroRNAs; Molecular; Molecular Biology; Molecular Genetics; Morbidity - disease rate; Muscle satellite cell; Mutation; Myeloproliferative disease; Oncogenes; Pathogenesis; Patients; Physicians; Pilot Projects; Polycythemia Vera; Production; Proteins; Public Health; Research; Research Personnel; Role; STAT1 gene; STAT5A gene; Scientist; Signal Transduction; Stem cells; Supportive care; Time; Training; Training Programs; Transfection; Up-Regulation; Veterans; Work; career; career development; design; disease phenotype; erythroid differentiation; experience; in vivo; induced pluripotent stem cell; inhibitor/antagonist; insight; knock-down; mortality; novel; novel diagnostics; novel therapeutics; oncology; peripheral blood; programs; research and development; skills; stem; success; thrombocytosis; tool

DESCRIPTION (provided by applicant): This proposal outlines a 5-year training plan designed to equip the applicant with tools that will foster her success as an academic investigator with a focus on hematopoiesis and myeloproliferative neoplasm (MPN) research. Applicant: She has completed rigorous clinical training in both internal medicine and hematology- oncology and has spent the past two years acquiring experience in both basic and clinical Hematology research in her prior mentors' laboratories. The proposed career development program has been designed to further develop the most novel aspects of her research and to promote her development into an independent physician-scientist. Mentors: The primary mentor, Dr. Christopher Cardozo, is a VA investigator and will provide day to day guidance about laboratory work and the career development of the applicant. Dr. Cardozo has 20 years experience in biochemistry and molecular biology and is internationally known for his contributions to our understanding of the molecular mechanism of androgen action on muscle stem cells, and recognized for his efforts in promoting research and development at the James J. Peters VA (JJPVA) Medical Center. The secondary mentor, Dr. Riccardo Dalla-Favera, is highly respected in the field of molecular genetics and internationally-recognized for his contribution to our understanding of oncogenes and microRNAs (miRNA) in hematologic malignancies. The secondary mentor Dr. Azra Raza is internationally known for landmark observations regarding the biology and treatment of MPNs. All three mentors are physician-scientists who have guided the successful development of many young investigators. The mentoring team will provide synergistic guidance about career development within the VA, laboratory methods, miRNA biology and MPN pathogenesis. The JJPVA Medical Center and its affiliate Columbia University Medical Center are deeply committed to the development of the applicant as an independent investigator. Research plan: The research plan follows naturally from the applicant's recent novel work generating a JAK2V617F-positive induced pluripotent stem (iPS) cell line from peripheral blood CD34+ cells from an MPN patient, and from a separate study which identified candidate miRNAs that may contribute to MPN stem cell pool expansion and hematopoietic lineage commitment. MiRNAs regulate hematopoiesis in both hematopoietic stem cells and committed progenitor cells. MPN is a stem cell disorder. However, there has been no miRNA expression analysis in MPN stem cells to date. Here, we propose to study the roles of these deregulated miRNAs in JAK2V617F-positive hematopoietic stem/progenitor cell expansion and hematopoietic lineage commitment. Both patient peripheral blood CD34+ cells and the JAk2V617F-positive iPS cell line will be used to study the candidate miRNAs' in vivo expression and in vitro function. The underlying mechanisms in hematopoietic cell signal transduction will also be explored. This training program will provide the applicant with valuable skills and will serve as the foundation for a successful career in translational hematology investigation. Relevance: MPNs represent an underserved group of disorders affecting veterans and non-veterans with significant disease- related morbidity and mortality. The only treatment currently available is supportive care. Significance: The proposed work will address this unique opportunity in the VA health care system and fill important gaps in our knowledge of miRNA deregulation in MPN stem cells which hold the potential to promote the development of novel diagnostic and therapeutic capabilities in MPN.

描述（由申请人提供）： 该提案概述了一个为期5年的培训计划，旨在为申请人提供工具，以促进她作为学术研究者的成功，重点是造血和骨髓增生性肿瘤（MPN）研究。申请人：她已经完成了严格的内科和血液肿瘤学临床培训，并在过去两年中在她以前的导师实验室获得了基础和临床血液学研究的经验。拟议的职业发展计划旨在进一步发展她的研究的最新方面，并促进她发展成为一个独立的医生，科学家。导师：克里斯托弗·卡多佐博士是VA调查员，将提供有关实验室工作和申请人职业发展的日常指导。Cardozo博士在生物化学和分子生物学方面拥有20年的经验，并因其对我们理解雄激素对肌肉干细胞作用的分子机制的贡献而享誉国际，并因其在促进James J. Peters VA（JJPVA）医学中心的研究和开发方面所做的努力而受到认可。Riccardo Dalla-Favera博士在分子遗传学领域备受尊敬，并因其对我们理解血液恶性肿瘤中的癌基因和microRNA（miRNA）的贡献而受到国际认可。二级导师Azra Raza博士因其对MPN生物学和治疗的里程碑式观察而享誉国际。这三位导师都是医学科学家，他们指导了许多年轻研究人员的成功发展。指导团队将提供有关VA，实验室方法，miRNA生物学和MPN发病机制内的职业发展的协同指导。JJPVA医学中心及其附属哥伦比亚大学医学中心致力于将申请人培养为独立研究者。研究计划：该研究计划自然遵循申请人最近的新工作，其从来自MPN患者的外周血CD 34+细胞产生JAK 2 V617 F阳性诱导多能干（iPS）细胞系，并且来自鉴定可能有助于MPN干细胞库扩增和造血谱系定型的候选miRNA的单独研究。MiRNA调节造血干细胞和定向祖细胞中的造血。MPN是一种干细胞疾病。然而，迄今为止，在MPN干细胞中还没有miRNA表达分析。在这里，我们建议研究这些失调的miRNA在JAK 2 V617 F阳性造血干/祖细胞扩增和造血谱系定型中的作用。患者外周血CD 34+细胞和JAk 2 V617 F阳性iPS细胞系将用于研究候选miRNA的体内表达和体外功能。造血细胞信号转导的潜在机制也将被探讨。该培训计划将为申请人提供有价值的技能，并将作为成功的职业生涯在翻译血液学研究的基础。相关性：MPN代表了一组影响退伍军人和非退伍军人的疾病，具有显著的疾病相关的发病率和死亡率。目前唯一可用的治疗方法是支持性护理。重要性：拟议的工作将解决VA医疗保健系统中的这一独特机会，并填补我们对MPN干细胞中miRNA失调的认识中的重要空白，这有可能促进MPN新型诊断和治疗能力的发展。