UMGCC Research Program:
Experimental Therapeutics Program
Education/Training:
College Degree:
M.S., University of Buenos Aires, School of Pharmacy and Biochemistry
Ph.D., New York University School of Medicine, Cell Biology
Post Doctoral
Degree:
Rockefeller University
Contact
Information:
Mailing Address:
University of Maryland
School of Medicine
Department of Microbiology and Immunology
Howard Hall, Room 319C
Baltimore, Maryland 21201
Email:
rfeldman@umaryland.edu
Phone:
410-706-4198
Fax:
410-706-2129
Research Interests:
Our laboratory uses the tools of molecular genetics to study the self-renewal, mobilization, differentiation and tissue regeneration properties of adult and embryonic stem cells. In one of our projects we use transgenic mice (SCL-TVA) that allow targeted delivery of genes to hematopoietic and vascular endothelial stem cells in the intact animal. This is done by injection of SCL-TVA mice with tissue-specific retroviral vectors that home to stem cells in their bone marrow niche. One application of this gene delivery system is in vivo labeling of long-term self-renewing stem cells with markers such as luciferase and EGFP. This allowed us to visualize the location of hemangioblasts and hematopoietic stem cells in their natural locations by bioluminescence imaging of live animals, and to follow the fate and mobilization of these stem cells in response to injury or biotherapeutic agents, in real time. In another application we delivered an oncogene to bone marrow stem cells in vivo, and recapitulated the first steps in the conversion of hemangioblasts to hemangioma stem cells that occur in pediatric and adult hemangiomas. We found that this oncogenic event involved the activation of the PI 3-kinase and the Rapamycin-sensitive mTor pathways. The ability to deliver regulatory genes and shRNAs to stem cells will be used to identify the critical signaling molecules that regulate self-renewal, mobilization and differentiation of stem cells in an in vivo model, and in real time. This flexible experimental system circumvents the problems associated with conventional in vitro manipulation of bone marrow stem cells and transplantation into lethally irradiated animals.
Another major interest of our laboratory is the generation of disease-specific human embryonic stem cells, for modeling and treating Gaucher's disease. This is the most frequent inherited lipid-storage disorder, and is caused by mutations in the acid beta-glucocerebrosidase gene. This enzyme deficiency results in the accumulation of glucosylceramide in the lysosomes of macrophages and other cells of the reticuloendothelial system. The accumulation of lipid in lysosomes leads to hepatomegaly, splenomegaly, hematologic abnormalities, bone disease, and in some cases neurological involvement. Disease modeling is done by two different approaches. One involves knockdown of the glucocerebrosidase gene using shRNA-encoding lentiviruses. The other is based on the reprogramming of fibroblasts from Gaucher patients harboring mutations in the glucocerebrosidase gene, into induced pluripotent stem (iPS) cells. As iPS cells can give rise to any cell type, their controlled differentiation into the affected cell types provides an unlimited supply of patient-specific cells for disease modeling and drug discovery. Our ultimate goal is to repair the genetic defect of the Gaucher-specific iPS cells, differentiate them into long-term self-renewing hemangioblasts, and engraft repaired autologous hemangioblasts into patients for cure of the disease.
Publications:
Xie, Y., Yin, T., Wiegraebe, W., He, X.C., Miller, D., Stark, D., Perko, K., Alexander, R., Schwartz, J., Grindley, J., Park, J., Haug, J., Wunderlich, J., Li, H., Zhang, S., Johnson, T., Feldman, RA, and Li, L. 2009. Detection of functional hematopoietic stem cell niche using real-time imaging. Nature, 457: 97-101.
Sausville J., Molinolo, A., Cheng, X., Frampton, J., Takebe N., Gutkind, J.S., and Feldman, RA. 2008. RCAS/SCL-TVA animal model allows targeted delivery of PyMT oncogene to vascular endothelial progenitors in vivo, and results in hemangioma development. Clin. Cancer Res. 14: 3948-3955.
Kim, J., Ogata, Y., Ali, H., and Feldman, RA. 2004. The Fes tyrosine kinase: a signal transducer that regulates myeloid-specific gene expression through transcriptional activation. Blood Cells Mol Dis. 32: 302-308.
Kim, J., Ogata, Y., and Feldman, RA. 2003. Fes tyrosine kinase promotes survival and terminal granulocyte differentiation of factor-dependent myeloid progenitors (32D) and activates lineage-specific transcription factors. J. Biol. Chem. 278: 14978-14984.
Kim, J., and Feldman, RA. 2002. Activated Fes Protein Tyrosine Kinase Induces Terminal Macrophage Differentiation of Myeloid Progenitors (U937 cells) and Activation of the Transcription factor PU.1. Mol. Cell. Biol. 22: 1903-1918.
Jücker, M., Südel, K., Horn, S., Sickel, M., Wegner, W., Fiedler, W., and Feldman, RA. 2002. Expression of a mutated form of the p85 alpha regulatory subunit of phosphatidylinositol 3-kinase in a Hodgkin's lymphoma-derived cell line (CO). Leukemia 16: 894-901.
Hackenmiller, R., Kim, J., Feldman, RA., and Simon, M. C. 2000. Abnormal STAT activation, hematopoietic homeostasis and innate immunity in c-fes-/- mice. Immunity 13: 397-407.
