Analysis of mDia formins in hematopoietic stem cell engraftment and migration

Summary

Principal Investigator: Peng Ji
Abstract: I am a MD/PhD postdoctoral scientist with extensive training in molecular and cell biology from Albert Einstein College of Medicine and Whitehead Institute. My research focuses on the roles of the mDia formin proteins on hematopoietic cells. The mDia formin proteins have well-established roles on the migration of many different cell types. However, their effects on the migration of hematopoietic cells, especially hematopoietic stem cells (HSCs), are poorly understood. With the ideal research environment of Whitehead Institute and excellent mentorship of Dr. Harvey Lodish, I plan to expand my existing scientific and intellectual skills by developing expertise in areas of hematopoeitic stem cells and cell migration, which is vital to my long term career goal of becoming a successful, independent investigator. The goal of my proposed study is to characterize the functional roles of mDia formins, specifically mDia1 and mDia2, on hematopoietic stem cell (HSC) engraftment and migration. HSC engraftment and migration are critical for successful bone marrow transplantation, which has become a routine clinical strategy for treating patients with many blood related diseases such as aplastic anemia, fanconi anemia, sickle cell anemia, beta thalassemia major, leukemia, lymphomas, multiple myeloma, and many immune deficiency disorders. The intracellular signaling pathways regulating HSC engraftment and migration often directly or indirectly target on the actin cytoskeleton network through proteins that regulate polymerization of the actin proteins. The mDia formin proteins are a major actin-nucleating family and their functions in HSCs are poorly understood. To elucidate the roles of mDia formins, specifically mDia1 and mDia2, on HSC migration, genetically modified mouse models and molecular cell biology techniques will be used. Specifically, mouse models deficient of mDia1 or mDia2 will be generated. With these mice, bone marrow and fetal liver Lin-Sca1+Kit+ (LSK) cells, an enriched HSC population, will be purified to perform in vitro migration assays, short-term homing, and long- term engraftment analysis. In collaboration with Drs. Tzutzuy Ramirez Hernandez and Maki Murata-Hori of the Temasek Life Sciences Laboratory in Singapore, the kinetic interactions of mDia1 and mDia2 with actin cytoskeletal proteins and how these interactions regulate hematopoietic stem cell migration will be investigated using confocal fluorescent microscopy and mass spectrometry analysis. In addition, post-translational modifications of mDia1 and mDia2, especially acetylation and phosphorylation, and how these modifications affect their functions in HSC migration will also be characterized.
Funding Period: 2010-06-01 - 2015-05-31
more information: NIH RePORT

Top Publications

  1. pmc Ankyrin and band 3 differentially affect expression of membrane glycoproteins but are not required for erythroblast enucleation
    Peng Ji
    Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
    Biochem Biophys Res Commun 417:1188-92. 2012
  2. pmc Mammalian erythroblast enucleation requires PI3K-dependent cell polarization
    Junxia Wang
    Temasek Life Sciences Laboratory, 1 Research Link, National University of Singapore, 117604 Singapore
    J Cell Sci 125:340-9. 2012

Research Grants

  1. HORMONAL REGULATION OF BLOOD PRESSURE
    Michal Laniado Schwartzman; Fiscal Year: 2013
  2. Pathophysiology of Alveolar Epithelial Lung Injury
    Jacob I Sznajder; Fiscal Year: 2013
  3. MECHANISMS OF SYNERGISTIC REGULATION OF STEM/PROGENITORS
    Hal E Broxmeyer; Fiscal Year: 2013
  4. Regulation of Acute Graft-versus-Host Disease by Coronins
    LESHARA MALIKA FULTON; Fiscal Year: 2013
  5. Epidemiology of Breast Cancer Subtypes in African American Women: a Consortium
    Julie R Palmer; Fiscal Year: 2013
  6. DEVELOPMENTAL BIOLOGY OF HUMAN ERYTHROPOIESIS
    Stuart H Orkin; Fiscal Year: 2013
  7. Mechanisms of State Switching in Sleep and Sleep Apnea
    Clifford B Saper; Fiscal Year: 2013
  8. Jules Stein Eye Institute Core Grant for Vision Research
    Wayne L Hubbell; Fiscal Year: 2013
  9. Intellectual and Development Disabilities Research Center
    Marc Yudkoff; Fiscal Year: 2013
  10. CSHL CANCER CENTER SUPPORT GRANT
    BRUCE W STILLMAN; Fiscal Year: 2013

Detail Information

Publications2

  1. pmc Ankyrin and band 3 differentially affect expression of membrane glycoproteins but are not required for erythroblast enucleation
    Peng Ji
    Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
    Biochem Biophys Res Commun 417:1188-92. 2012
    ..However, neither band 3 nor ankyrin are required for enucleation. These results demonstrate that mammalian erythroblast enucleation does not depend on the membrane integrity generated by the ankyrin-band 3 complex...
  2. pmc Mammalian erythroblast enucleation requires PI3K-dependent cell polarization
    Junxia Wang
    Temasek Life Sciences Laboratory, 1 Research Link, National University of Singapore, 117604 Singapore
    J Cell Sci 125:340-9. 2012
    ..We propose that enucleation is regulated by microtubules and PI3K signaling in a manner mechanistically similar to directed cell locomotion...

Research Grants30

  1. HORMONAL REGULATION OF BLOOD PRESSURE
    Michal Laniado Schwartzman; Fiscal Year: 2013
    ..ular tone, in the pathophysiology of hypertension and cardiovascular disease. ..
  2. Pathophysiology of Alveolar Epithelial Lung Injury
    Jacob I Sznajder; Fiscal Year: 2013
    ..The insights gained from the data generated from these studies will provide novel molecular targets for the development of new therapeutic strategies to treat patients with lung injury. ..
  3. MECHANISMS OF SYNERGISTIC REGULATION OF STEM/PROGENITORS
    Hal E Broxmeyer; Fiscal Year: 2013
    ....
  4. Regulation of Acute Graft-versus-Host Disease by Coronins
    LESHARA MALIKA FULTON; Fiscal Year: 2013
    ....
  5. 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. ..
  6. DEVELOPMENTAL BIOLOGY OF HUMAN ERYTHROPOIESIS
    Stuart H Orkin; Fiscal Year: 2013
    ..abstract_text> ..
  7. Mechanisms of State Switching in Sleep and Sleep Apnea
    Clifford B Saper; Fiscal Year: 2013
    ..This work will help to design interventions for improving the health of patients with OSA. ..
  8. Jules Stein Eye Institute Core Grant for Vision Research
    Wayne L Hubbell; Fiscal Year: 2013
    ..Support in the form of the Core grant is requested to maintain these Modules through instrument service contracts, and to provide necessary personnel support to assist and train users and provide routine maintenance. ..
  9. Intellectual and Development Disabilities Research Center
    Marc Yudkoff; Fiscal Year: 2013
    ..5 million from NICHD). The Center includes an excess of 70 Penn faculty at 15 departments at the Schools of Medicine, Veterinary Medicine, Nursing, the Wistar Institute, and the College of Arts and Sciences. ..
  10. CSHL CANCER CENTER SUPPORT GRANT
    BRUCE W STILLMAN; Fiscal Year: 2013
    ....
  11. Lnk Regulatory Functions in Hematopoietic Stem Cells
    Wei Tong; Fiscal Year: 2013
    ..We believe our studies will advance our understanding of the mechanisms underlying stem cell homeostasis and facilitate clinical applications to stem cell therapy. ..
  12. STEM CELL GENE THERAPY FOR HEMOGLOBINOPATHIES
    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) ..
  13. MLL Function in the Maintenance of the Blood Forming System
    PATRICIA A ERNST; Fiscal Year: 2013
    ..abstract_text> ..