The Stanford-Johns Hopkins Research Hub intends to gain a deeper understanding of molecular pathways to enhance the efficiency of nuclear reprogramming, to ensure the function and safety of induced pluripotentlal cells (iPSCs), to provide robust protocols for differentiation and purification of hematopoietic and endothelial lineages, and to guide pioneering work in pre-clinical studies of safety and efficacy. The Hopkins group proposes three research projects. PROJECT 1 (S. Baylin) proposes to characterize epigenetic events mediated by DNMT occuring during reprogramming to the stem cell fate and to manipulate these events to enhance reprogramming and avoid transformation. PROJECT 2 (E. Zambidis) proposes to characterize the human hemangioblast, taking advantage of the novel finding that this bipotent progenitor is expresses ACE, to manipulate ACE signaling to favor emergence of adult HSC, to utilize novel marrow stromal signals to favor emergence of adult HSC, and to determine the role of novel miRNAs identified as hemangioblast or HSC-specific in directing HSC specification. This project will also combine knowledge gained throughout our Hub and the Consortium to optimally generate and pre-clinically evaluate human IPSO and adult HSC. PROJECT 3 (A. Friedman) will identify the mechanisms allowing HSC specification by Runxl, a master transcriptional regulator of adult HSC emergence from hemogenic endothelium. The role of Runxl isoforms, Runxl phopshorylation, Runxl interaction with HDACs or Ets factors, and Runxl cooperation with Notch, Wnt, or BMP signaling will be evaluated. Identification of relevant Runxl genetic targets using global RNA expression and ChiP-chip or ChlP-Seq approaches will be undertaken, and expression analyses will seek novel regulators, expressed in HSC but not the hemangioblast. CORE activities conducted in collaboration with our Stanford colleagues will include epigenetic comparison of IPSC to cancer cells and to hESC (S. Baylin) and bioinformatics analysis of epigenetic, RNA expression, and ChIP data (L. Cope). We anticipate that these efforts will lead to basic insights in developmental biology and to novel, translational applications for hematologic and vascular disorders.
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