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: 8970682
• 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/8970682
• 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; 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; Scientist; Signal Transduction; Stat5 protein; 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; targeted treatment; 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)： 这份提案概述了一项为期5年的培训计划，旨在为申请者配备工具，以促进她作为一名专注于造血和骨髓增生性肿瘤(MPN)研究的学术研究人员取得成功。申请者：她已经完成了内科和血液肿瘤学的严格临床培训，并在过去的两年里在她以前导师的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中最新颖的方面，并促进她发展成为一名独立的内科科学家。导师：首席导师克里斯托弗·卡多佐博士是退伍军人管理局的一名调查员，他将就实验室工作和申请人的职业发展提供日常指导。卡多佐博士在生物化学和分子生物学方面拥有20年的经验，他为我们理解雄激素对肌肉干细胞作用的分子机制做出了贡献，并因在詹姆斯·J·彼得斯VA医学中心(JJPVA)促进研究和开发所做的努力而闻名国际。第二导师里卡多·达拉-法维拉博士在分子遗传学领域备受尊敬，并因其对我们对血液系统恶性肿瘤中癌基因和microRNAs(MiRNA)的理解做出了国际公认的贡献。副导师Azra Raza博士因在MPN的生物学和治疗方面的里程碑式的观察而闻名国际。这三位导师都是内科科学家，他们指导了许多年轻研究人员的成功发展。指导团队将就退伍军人管理局内的职业发展、实验室方法、miRNA生物学和MPN发病机制提供协同指导。JJPVA医学中心及其附属机构哥伦比亚大学医学中心致力于将申请者发展成为一名独立的调查者。研究计划：该研究计划自然源于申请人最近从一名MPN患者的外周血CD34+细胞中培养出JAK2V617F阳性诱导多能干细胞系的新工作，以及另一项确定可能有助于MPN干细胞库扩大和造血谱系承诺的候选miRNAs的研究。MiRNAs调节造血干细胞和定向祖细胞的造血。MPN是一种干细胞疾病。然而，到目前为止，还没有对MPN干细胞中miRNA的表达进行分析。在这里，我们建议研究这些非调控的miRNAs在JAK2V617F阳性的造血干/祖细胞扩张和造血谱系承诺中的作用。患者外周血CD34+细胞和JAK2V617F阳性iPS细胞株将用于研究候选miRNAs的体内表达和体外功能。还将探讨造血细胞信号转导的潜在机制。这一培训计划将为申请者提供宝贵的技能，并将作为在翻译血液学研究方面成功职业生涯的基础。相关性：MPN是一组服务不足的疾病，影响退伍军人和非退伍军人，具有与疾病相关的严重发病率和死亡率。目前唯一可用的治疗方法是支持性护理。意义：拟议的工作将解决退伍军人管理局医疗保健系统中的这一独特机会，并填补我们在MPN干细胞中miRNA放松调控方面的重要空白，这将具有促进MPN新诊断和治疗能力发展的潜力。

项目成果

MicroRNA deregulation in polycythemia vera and essential thrombocythemia patients.

真性红细胞增多症和原发性血小板增多症患者的 MicroRNA 失调。

• DOI: 10.1016/j.bcmd.2012.11.009
• 发表时间: 2013
• 期刊: Blood cells, molecules & diseases
• 作者: Zhan,Huichun;Cardozo,Christopher;Yu,Wayne;Wang,Antai;Moliterno,AlisonR;Dang,ChiV;Spivak,JerryL
• 通讯作者: Spivak,JerryL

Targeting glutamine metabolism in myeloproliferative neoplasms.

• DOI: 10.1016/j.bcmd.2015.07.007
• 发表时间: 2015-10
• 期刊: Blood cells, molecules & diseases
• 作者: H. Zhan;Kristen A Ciano;Katherine Dong;S. Zucker