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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01HL099775-05
Application #
8470692
Study Section
Special Emphasis Panel (ZHL1-CSR-J (S1))
Program Officer
Thomas, John
Project Start
2009-09-30
Project End
2016-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
5
Fiscal Year
2013
Total Cost
$1,159,250
Indirect Cost
$452,390
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Park, Tea Soon; Bhutto, Imran; Zimmerlin, Ludovic et al. (2014) Vascular progenitors from cord blood-derived induced pluripotent stem cells possess augmented capacity for regenerating ischemic retinal vasculature. Circulation 129:359-72
Park, Tea Soon; Donnenberg, Vera S; Donnenberg, Albert D et al. (2014) Dynamic Interactions Between Cancer Stem Cells And Their Stromal Partners. Curr Pathobiol Rep 2:41-52
Panicker, Leelamma M; Miller, Diana; Awad, Ola et al. (2014) Gaucher iPSC-derived macrophages produce elevated levels of inflammatory mediators and serve as a new platform for therapeutic development. Stem Cells 32:2338-49
Ma, Ou; Hong, SunHwa; Guo, Hong et al. (2014) Granulopoiesis requires increased C/EBP? compared to monopoiesis, correlated with elevated Cebpa in immature G-CSF receptor versus M-CSF receptor expressing cells. PLoS One 9:e95784
Easwaran, Hariharan; Tsai, Hsing-Chen; Baylin, Stephen B (2014) Cancer epigenetics: tumor heterogeneity, plasticity of stem-like states, and drug resistance. Mol Cell 54:716-27
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
Zhong, Xiufeng; Gutierrez, Christian; Xue, Tian et al. (2014) Generation of three-dimensional retinal tissue with functional photoreceptors from human iPSCs. Nat Commun 5:4047
Gorospe, Giann; Zhu, Renjun; Millrod, Michal A et al. (2014) Automated grouping of action potentials of human embryonic stem cell-derived cardiomyocytes. IEEE Trans Biomed Eng 61:2389-95
Zimmerlin, Ludovic; Park, Tea Soon; Zambidis, Elias T et al. (2013) Mesenchymal stem cell secretome and regenerative therapy after cancer. Biochimie 95:2235-45
Rufaihah, Abdul Jalil; Huang, Ngan F; Kim, Jeanna et al. (2013) Human induced pluripotent stem cell-derived endothelial cells exhibit functional heterogeneity. Am J Transl Res 5:21-35

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