Over 1 million Americans suffer acute myocardial infarctions each year in the US, and among the survivors, 5 million are afflicted with heart failure. In addition, defects in cell lineage determination or morphogenesis underlie congenital heart malformations, the most common human birth defect. Survivors of congenital heart disease, who number over 1 million in the US, also often suffer from heart failure. Unfortunately, the heart has little regenerative capacity after injury. The recent discovery of human induced pluripotent stem (IPS) cells has opened the door for novel approaches to human disease, including the development of human cellular models for disease mechanisms and drug discovery, along with the potential for autologous cell-based therapies. We propose to assemble a team of investigators at the Gladstone Institutes and Stanford University to develop and capitalize on the potential of IPS cells in the treatment and understanding of heart disease. Methods of IPS generation avoiding genomic integration of DNA are developing rapidly, but continue to require refinement before use of iPS cells in humans;this hurdle will be addressed in this application. As methods for generating IPS cells are improved the team will work together to more efficiently generate iPS-derived cardiac cells for future therapy, capitalizing on their expertise in chromatin remodeling and microRNA (miRNA) biology and G-protein coupled receptor signaling. The team will generate iPS cell lines with fluorescent markers for progressive stages of cardiac differentiation using bacterial artificial chromosome (BAC) strategies. We will also attempt to reprogram somatic cells directly into cardiac progenitors. Survival and engraftment of cells in vivo will be examined in rodents and in large animals through our partners at Stanford. Disease-specific iPS cells will be generated to reveal novel aspects of human progenitor cell biology. This multidisciplinary team will bring broad and critical expertise to the NHLBI Progenitor Cell Consortium in an effort to aggressively capitalize on the promise and potential of iPS cells for heart disease The interaction with the Stanford group within our Hub will synergize and leverage the specific strengths of each group of investigators on the focused effort related to iPS cells.
The specific aims are: 1) To develop integration-free and efficient methods of human IPS cell generation for future cell-based therapies;2) To develop efficient directed differentiation of human IPS cells and methods of direct reprogramming;3). To develop methods to use IPS cell-derived cardiac progenitors in animal models of cardiovascular disease and 4). To use disease-specific IPS cells for discovery of human cardiac progenitor biology and cardiovascular disease mechanisms.
|Theodoris, Christina V; Mourkioti, Foteini; Huang, Yu et al. (2017) Long telomeres protect against age-dependent cardiac disease caused by NOTCH1 haploinsufficiency. J Clin Invest 127:1683-1688|
|Judge, Luke M; Perez-Bermejo, Juan A; Truong, Annie et al. (2017) A BAG3 chaperone complex maintains cardiomyocyte function during proteotoxic stress. JCI Insight 2:|
|Mohamed, Tamer M A; Stone, Nicole R; Berry, Emily C et al. (2017) Chemical Enhancement of In Vitro and In Vivo Direct Cardiac Reprogramming. Circulation 135:978-995|
|Liu, S John; Horlbeck, Max A; Cho, Seung Woo et al. (2017) CRISPRi-based genome-scale identification of functional long noncoding RNA loci in human cells. Science 355:|
|Huebsch, Nathaniel; Loskill, Peter; Deveshwar, Nikhil et al. (2016) Miniaturized iPS-Cell-Derived Cardiac Muscles for Physiologically Relevant Drug Response Analyses. Sci Rep 6:24726|
|Ang, Yen-Sin; Rivas, Renee N; Ribeiro, Alexandre J S et al. (2016) Disease Model of GATA4 Mutation Reveals Transcription Factor Cooperativity in Human Cardiogenesis. Cell 167:1734-1749.e22|
|Mandegar, Mohammad A; Huebsch, Nathaniel; Frolov, Ekaterina B et al. (2016) CRISPR Interference Efficiently Induces Specific and Reversible Gene Silencing in Human iPSCs. Cell Stem Cell 18:541-53|
|Miyaoka, Yuichiro; Berman, Jennifer R; Cooper, Samantha B et al. (2016) Systematic quantification of HDR and NHEJ reveals effects of locus, nuclease, and cell type on genome-editing. Sci Rep 6:23549|
|Kime, Cody; Mandegar, Mohammad A; Srivastava, Deepak et al. (2016) Efficient CRISPR/Cas9-Based Genome Engineering in Human Pluripotent Stem Cells. Curr Protoc Hum Genet 88:Unit 21.4|
|Kime, Cody; Sakaki-Yumoto, Masayo; Goodrich, Leeanne et al. (2016) Autotaxin-mediated lipid signaling intersects with LIF and BMP signaling to promote the naive pluripotency transcription factor program. Proc Natl Acad Sci U S A 113:12478-12483|
Showing the most recent 10 out of 47 publications