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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZHL1-CSR-J (S1))
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Thomas, John
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Johns Hopkins University
Internal Medicine/Medicine
Schools of Medicine
United States
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McMahan, Zsuzsanna H; Cottrell, Tricia R; Wigley, Fredrick M et al. (2016) Enrichment of Scleroderma Vascular Disease-Associated Autoantigens in Endothelial Lineage Cells. Arthritis Rheumatol 68:2540-9
Nagaria, Pratik K; Robert, Carine; Park, Tea Soon et al. (2016) High-Fidelity Reprogrammed Human IPSCs Have a High Efficacy of DNA Repair and Resemble hESCs in Their MYC Transcriptional Signature. Stem Cells Int 2016:3826249
Leong, Wan Yee; Guo, Hong; Ma, Ou et al. (2016) Runx1 Phosphorylation by Src Increases Trans-activation via Augmented Stability, Reduced Histone Deacetylase (HDAC) Binding, and Increased DNA Affinity, and Activated Runx1 Favors Granulopoiesis. J Biol Chem 291:826-36
Salomonis, Nathan; Dexheimer, Phillip J; Omberg, Larsson et al. (2016) Integrated Genomic Analysis of Diverse Induced Pluripotent Stem Cells from the Progenitor Cell Biology Consortium. Stem Cell Reports 7:110-25
Zhu, Renjun; Millrod, Michal A; Zambidis, Elias T et al. (2016) Variability of Action Potentials Within and Among Cardiac Cell Clusters Derived from Human Embryonic Stem Cells. Sci Rep 6:18544
Guo, Hong; Cooper, Stacy; Friedman, Alan D (2016) In Vivo Deletion of the Cebpa +37 kb Enhancer Markedly Reduces Cebpa mRNA in Myeloid Progenitors but Not in Non-Hematopoietic Tissues to Impair Granulopoiesis. PLoS One 11:e0150809
Zhang, Jing; Li, Li; Baldwin Jr, Albert S et al. (2015) Loss of IKKβ but Not NF-κB p65 Skews Differentiation towards Myeloid over Erythroid Commitment and Increases Myeloid Progenitor Self-Renewal and Functional Long-Term Hematopoietic Stem Cells. PLoS One 10:e0130441
Cooper, Stacy; Guo, Hong; Friedman, Alan D (2015) The +37 kb Cebpa Enhancer Is Critical for Cebpa Myeloid Gene Expression and Contains Functional Sites that Bind SCL, GATA2, C/EBPα, PU.1, and Additional Ets Factors. PLoS One 10:e0126385
Sgambato, Judi A; Park, Tea Soon; Miller, Diana et al. (2015) Gaucher Disease-Induced Pluripotent Stem Cells Display Decreased Erythroid Potential and Aberrant Myelopoiesis. Stem Cells Transl Med 4:878-86
Guo, Hong; Ma, Ou; Friedman, Alan D (2014) The Cebpa +37-kb enhancer directs transgene expression to myeloid progenitors and to long-term hematopoietic stem cells. J Leukoc Biol 96:419-26

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