Our laboratory is using human induced pluripotent stem cells (hiPSC) for disease modeling and drug discovery. By viral-mediated introduction of the 4 Yamanaka factors (Oct4, Sox2, Klf4 and c-Myc) we have reprogrammed patient fibroblasts into hiPSC representative of all 3 clinical subtypes of Gaucher disease. This is the most frequent inherited lipid-storage disease, and is caused by mutations in the acid beta-glucocerebrosidase gene. This enzyme deficiency results in the accumulation of glucosylsphingolipids in lysosomes of the affected cell types, including macrophages and neuronal cells. The enzyme deficiency in Gaucher macrophages leads to hepatosplenomegaly, hematologic abnormalities and bone disease. The more severe mutations in types 2 and 3 Gaucher disease also cause neurological abnormalities that are fatal. By directed differentiation of patient-derived hiPSC to the affected cell types, we have recapitulated the characteristic hallmarks of the disease and obtained new insights with important clinical implications (Panicker et al.). We found that the abnormal phenotype of Gaucher cells is not merely due to an accumulation of lipid but that there is a defect in intracellular membrane transport that blocks the flow of cargo (phagocytosed material, protein aggregates, organelles for recycling) to the lysosome. We found that the extent of the blockage is inversely correlated to the severity of the mutations, reflecting clinical observations. Using the hiPSC-derived relevant cell types we have developed novel functional assays that recapitulate the known clinical efficacies of therapeutic agents used to treat the disease. Our laboratory is using the tools of molecular genetics and imaging analysis to elucidate the precise steps that are blocked in the lysosomal cascade. Phenotypic abnormalities are correlated with specific mutations and clinical manifestations. It was recently found that 10% of all Parkinson disease cases have mutations in glucocerebrosidase, indicating that the importance of this enzyme extends well beyond Gaucher disease. Our laboratory is also using hiPSC-neurons exhibiting certain genetic polymorphisms from addicted individuals, for modeling and treatment of nicotine addiction. Other work in the laboratory involves the use of transgenic mice (SCL-TVA) that allow targeted delivery of genes to hematopoietic and vascular endothelial stem cells in the intact animal. One application of this gene delivery system is in vivo labeling of long-term self-renewing stem cells with markers such as luciferase (Xie et al.). 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. This flexible experimental system circumvents the problems associated with conventional in vitro manipulation of bone marrow stem cells and transplantation into lethally irradiated animals.
A postdoctoral position is available in the Department of Microbiology and Immunology at the University of Maryland School of Medicine, to model inherited lipid storage diseases using iPS cell technology. Patient-derived iPS cells will be differentiated into hematopoietic and neuronal lineages and used to study the molecular mechanisms leading to abnormal cell function, and to develop gene- and stem cell-based therapy. The candidate should have a PhD, experience in Molecular and Cell Biology, excellent oral and written communication skills, and be able to work independently. Experience in hES/iPS cell technology and hematopoietic or neural development is desirable. Our laboratory is part of the newly established Center for Stem Cell Biology & Regenerative Medicine at UMB. This is an excellent opportunity for broad-based training in reprogramming biology and regenerative medicine. Salary is commensurate with experience. To apply, please send resume and contact information for three references to Dr. Ricardo A. Feldman.
Panicker L.M., Miller D., Park T.S., Patel B., Azevedo J.L., Awad O., Masood, M.A., Veenstra, T.D., Goldin E., Stubblefield, B., Tayebi, N., Polumuri S.K., Vogel S.N., Sidransky, E., Zambidis E.T., and Feldman R.A. (2012). Induced pluripotent stem cell model recapitulates pathologic hallmarks of Gaucher disease. Proc Natl Acad Sci USA. 109: 18054-9.
Azevedo, J.L., and Feldman, R.A. Tinkering with transcription factors uncovers plasticity of somatic cells. (2010). Genes & Cancer 1: 1089-99.
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.
- Comment in Nature Reports Stem Cells: Published online 15 January (2009).
- Comment in Cell, 136: 7 (2009).
Sausville J., Molinolo, A., Cheng, X., Frampton, J., Takebe N., Gutkind, J.S., and Feldman, RA. RCAS/SCL-TVA animal model allows targeted delivery of PyMT oncogene to vascular endothelial progenitors in vivo, and results in hemangioma development. 2008. 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.
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