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: 8332425
• 负责人: Huichun Zhan
• 金额: --
• 依托单位: JAMES J PETERS 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/8332425
• 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. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE Chronic myeloproliferative neoplasms (MPNs) include three distinct disorders each of which affects patients at all ages. These disorders have diverse and overlapping clinical manifestations, which often confounds their diagnosis. Because of the lack of a specific diagnostic test, their diagnosis is often delayed, leading to significant disease-related complications. Deficits in our understanding of MPN also contribute to the lack of effective targeted therapy; currently, treatment options are limited to supportive care. Knowledge regarding the molecular and cellular processes to aid better diagnosis and therapy is thus highly relevant to public health.

描述（由申请人提供）： 该提案概述了一项为期 5 年的培训计划，旨在为申请人提供工具，以促进她作为一名专注于造血和骨髓增生性肿瘤 (MPN) 研究的学术研究者取得成功。申请人：她已经完成了内科和血液肿瘤学方面严格的临床培训，并在过去两年中在其先前导师的实验室中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研究中最新颖的方面，并促进她发展成为一名独立的医师科学家。导师：主要导师 Christopher Cardozo 博士是一名 VA 调查员，将为申请人提供有关实验室工作和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 年经验，因其在理解雄激素对肌肉干细胞作用的分子机制方面的贡献而享誉国际，并因其在促进 James J. Peters 的研究和开发方面所做的努力而受到认可VA (JJPVA) 医疗中心。第二导师 Riccardo Dalla-Favera 博士在分子遗传学领域备受尊敬，并因对血液恶性肿瘤中癌基因和 microRNA (miRNA) 的理解做出的贡献而获得国际认可。二级导师 Azra Raza 博士因对 MPN 的生物学和治疗具有里程碑意义的观察而闻名于世。三位导师都是医学科学家，他们指导了许多年轻研究者的成功发展。指导团队将为 VA 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 医学中心及其附属哥伦比亚大学医学中心坚定致力于申请人作为独立研究者的发展。研究计划：该研究计划自然源自申请人最近的新工作，即从 MPN 患者的外周血 CD34+ 细胞中生成 JAK2V617F 阳性诱导多能干 (iPS) 细胞系，以及另一项单独的研究，该研究确定了可能有助于MPN 干细胞库扩张和造血谱系定型。 miRNA 调节造血干细胞和定向祖细胞的造血作用。 MPN 是一种干细胞疾病。然而，迄今为止尚未对 MPN 干细胞中的 miRNA 表达进行分析。在这里，我们建议研究这些失调的 miRNA 在 JAK2V617F 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CD34+细胞和JAk2V617F阳性iPS细胞系将用于研究候选miRNA的体内表达和体外功能。还将探索造血细胞信号转导的潜在机制。该培训计划将为申请人提供宝贵的技能，并将成为转化血液学研究职业成功的基础。相关性：MPN 代表了一组影响退伍军人和非退伍军人且服务不足的疾病，具有显着的疾病相关发病率和死亡率。目前唯一可用的治疗方法是支持治疗。意义：拟议的工作将解决 VA 医疗保健系统中的这一独特机会，并填补我们在 MPN 干细胞中 miRNA 失调的知识方面的重要空白，这有可能促进 MPN 新型诊断和治疗能力的发展。 公共卫生相关性： 项目叙述 慢性骨髓增生性肿瘤 (MPN) 包括三种不同的疾病，每种疾病都会影响所有年龄段的患者。这些疾病具有多样且重叠的临床表现，这常常会混淆其诊断。由于缺乏特定的诊断测试，他们的诊断常常被延迟，导致严重的疾病相关并发症。我们对 MPN 理解的缺陷也导致缺乏有效的靶向治疗；目前，治疗选择仅限于支持性护理。因此，有关分子和细胞过程的知识有助于更好的诊断和治疗，与公共卫生高度相关。