MicroRNA Deregulation in JAK2V617F-positive Chronic Myeloid Neoplasms


Principal Investigator: Huichun Zhan
Abstract: 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.
Funding Period: 2012-04-01 - 2017-03-31
more information: NIH RePORT

Research Grants

Detail Information

Research Grants30

  1. Functional and Molecular Dissection of Myeloproliferative Neoplasm Stem Cells
    Ann Mullally; Fiscal Year: 2013
    ..Finally, the candidate has recruited Dr. Ross Levine, one of the initial scientific investigators to describe the JAK2V617F mutation in MPN, as a collaborator for her project. ..
  2. Epidemiology of Breast Cancer Subtypes in African American Women: a Consortium
    Julie R Palmer; Fiscal Year: 2013
    ..By pooling our data, specimens, and importantly, expertise to investigate these synergist hypotheses, we will elucidate much of the etiology of aggressive, early onset breast cancers in AA women. ..
    Michal Laniado Schwartzman; Fiscal Year: 2013
    ..ular tone, in the pathophysiology of hypertension and cardiovascular disease. ..
    DAVID MORSE LIVINGSTON; Fiscal Year: 2013
    ..The goal of this Program is to continue to shed new light on cellular transformation events that also underpin human cancer development and generate insights that lead to new cancer therapeutic strategies. ..
  5. Arterial Dysfunction: Basic and Clinical Mechanisms
    Thomas Michel; Fiscal Year: 2013
    ..Gladyshev. P. Libby directs the Redox Biomarkers Core;metabolic characterizations of mouse models studied in this Program will take place at the Yale Mouse Metabolic Phenotyping Center, led by G. Shulman. ..
  6. Characterization of Genetic Abnormalities in MDS and Their Clinical Impact
    Rafael Bejar; Fiscal Year: 2013
    ..Successful completion the specific aims and career development plan outlined in this proposal will allow the candidate to advance his academic career as an independent investigator in the field of hematology. ..
  7. Molecular Pathways to Thynmic Lymphoma and Leukemia
    A Thomas Look; Fiscal Year: 2013
    ..Such interactions are expected to accelerate the pace at which important discoveries are generated in these projects and in the program as a whole. ..
    George Stamatoyannopoulos; Fiscal Year: 2013
    ..The focus of this Program Project, Gene Therapy, can provide a new paradigm for the treatment of these hemoglobinopathies as well as for other blood diseases. (End of Abstract) ..
    BRUCE W STILLMAN; Fiscal Year: 2013
  10. The Boston Area Diabetes Endocrinology Research Center
    Joseph Avruch; Fiscal Year: 2013
    ..abstract_text> ..
  11. Functional Genomic Dissection of Refractory Anemia
    BENJAMIN LEVINE EBERT; Fiscal Year: 2013
    ..In aggregate, these experiments will provide critical insight into the molecular basis of myelodysplastic syndrome. ..
  12. Hyaluronan Matrices in Vascular Pathologies
    Vincent C Hascall; Fiscal Year: 2013
    ..abstract_text> ..