Grant Award Details
- The objective of shared lab is to provide a resource to the stem cell community, including training, use of cell lines and equipment.
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Grant Application Details
- Center for hESC Research
The therapeutic use of stem cells in regenerative medicine will require the ability to control stem cell expansion and differentiation into specific tissue types, such as pancreatic ?-cells, heart tissue, bone or specific neuronal lineages. We have taken a chemical approach toward this problem in which large collections of synthetic small molecules are being screened in cell-based assays to identify drug-like molecules that control stem cell processes. Preliminary experiments in our institute have demonstrated that we can identify molecules that control the self-renewal and directed differentiation of murine embryonic stem cells. The characterization of the biological mechanisms of the molecules has also provided new insights into the underlying biology of stem cells. We now propose to extend these studies to hESC lines not eligible for federal funding, for which our research activities have been restricted to date. In addition, such lines may be better suited for specific applications, including the use of small molecules to derive specific cell lineages and investigate ES derived cell-based models of genetic disease. To this end, we would like to establish a human embryonic stem cell core facility. This facility will house the necessary equipment to genetically manipulate and culture hESCs on a large scale for a variety of studies including cell-based screens of small molecule libraries, as well as screens of arrayed genomic cDNA and siRNA libraries. We anticipate that this facility will serve our faculty as well as other labs that would like to collaboratively exploit this chemical approach to the study and manipulation of stem cells.
Historically, small molecules have been more useful than genetic approaches in the treatment of human disease. However, much of our ability to control embryonic stem cell self-renewal and directed differentiation currently involves genetic manipulation of these cells or complex mixtures of protein factors. The demonstration that one can systematically identify, optimize and characterize the mechanism of action of small drug-like molecules that selectively control stem cell biology both in vitro and in vivo will: (1) provide important tools to manipulate stem cells in the lab; (2) provide new insights into the complex biology that regulates stem cell differentiation; and (3) provide an important first step which may ultimately lead to drugs that facilitate the clinical application of stem cells.
Publications
- Brain (2017) Molecular analyses of neurogenic defects in a human pluripotent stem cell model of fragile X syndrome. (PubMed: 28137726)
- Stem Cells (2017) Spontaneous Single-Copy Loss of TP53 in Human Embryonic Stem Cells Markedly Increases Cell Proliferation and Survival. (PubMed: 27888558)
- Bioessays (2016) The tumorigenic potential of pluripotent stem cells: What can we do to minimize it? (PubMed: 27417126)
- Nat Commun (2016) Whole-genome mutational burden analysis of three pluripotency induction methods. (PubMed: 26892726)
- Zoo Biol (2016) Rewinding the process of mammalian extinction. (PubMed: 27142508)
- Proc Natl Acad Sci U S A (2015) HDAC inhibition imparts beneficial transgenerational effects in Huntington's disease mice via altered DNA and histone methylation. (PubMed: 25535382)
- Development (2015) Human stem cells from single blastomeres reveal pathways of embryonic or trophoblast fate specification. (PubMed: 26483210)
- Methods Mol Biol (2015) Generation of Induced Pluripotent Stem Cells from Mammalian Endangered Species. (PubMed: 26621593)
- Sci Rep (2015) Glycosyltransferase ST6GAL1 contributes to the regulation of pluripotency in human pluripotent stem cells. (PubMed: 26304831)
- Elife (2015) A panel of induced pluripotent stem cells from chimpanzees: a resource for comparative functional genomics. (PubMed: 26102527)
- Epigenomics (2015) DNA methylation fingerprint of neuroblastoma reveals new biological and clinical insights. (PubMed: 26067621)
- Genome Res (2015) Dynamic changes in replication timing and gene expression during lineage specification of human pluripotent stem cells. (PubMed: 26055160)
- Expert Opin Biol Ther (2015) The 'sweet' spot of cellular pluripotency: protein glycosylation in human pluripotent stem cells and its applications in regenerative medicine. (PubMed: 25736263)
- PLoS One (2015) Increased risk of genetic and epigenetic instability in human embryonic stem cells associated with specific culture conditions. (PubMed: 25714340)
- Stem Cells Transl Med (2015) Enabling consistency in pluripotent stem cell-derived products for research and development and clinical applications through material standards. (PubMed: 25650438)
- Mov Disord (2015) Stem cell reprogramming: basic implications and future perspective for movement disorders. (PubMed: 25546831)
- Nat Commun (2014) Role of astroglia in Down's syndrome revealed by patient-derived human-induced pluripotent stem cells. (PubMed: 25034944)
- Nature (2014) Network biology: A compass for stem-cell differentiation. (PubMed: 25254472)
- Expert Rev Neurother (2014) Promoting remyelination: utilizing a viral model of demyelination to assess cell-based therapies. (PubMed: 25245576)
- Genomics (2014) Application of a low cost array-based technique - TAB-Array - for quantifying and mapping both 5mC and 5hmC at single base resolution in human pluripotent stem cells. (PubMed: 25179373)
- Ann Neurol (2014) Epigenetic therapy for Friedreich ataxia. (PubMed: 25159818)
- Stem Cell Res Ther (2014) Neural stem cells genetically-modified to express neprilysin reduce pathology in Alzheimer transgenic models. (PubMed: 25022790)
- Circ Res (2014) Epigenetic regulation of pluripotency and differentiation. (PubMed: 24989490)
- Science (2014) Research capacity. Enabling the genomic revolution in Africa. (PubMed: 24948725)
- Tissue Eng Part A (2014) A global assessment of stem cell engineering. (PubMed: 24428577)