Lab information [ Lab website | CIRM grants ]
Heart failure is a very common and chronic condition defined by an inability of the heart to pump blood effectively. Over half of cases of heart failure are caused by a condition called dilated cardiomyopathy, which involves dilation of the heart cavity and weakening of the muscle. Importantly, many cases of this disease do not have a known cause and are called "idiopathic" (i.e., physicians do not know why). Over the past 2 decades, doctors and scientists started realizing the disease can cluster in families, leading them to think there is a genetic cause to the disease. This resulted in discovering multiple genes that cause this disease. Nonetheless, the majority of cases of dilated hearts that cluster in families do not have a known genetic cause. Now scientists can turn blood and skin cells into heart cells by genetically manipulating them and creating engineered stem cells called "induced pluripotent stem cells" or iPSCs. This approach enables the scientists to study what chemical or genetic changes are happening to cause the problem. Also because these cells behave similar to the cells in the heart, scientists can now test new medicines on these cells first before trying them in patients.
The goal of this project is to establish a biobank of extensively well-characterized iPSC lines and to validate the utility of this resource by modeling two highly prevalent familial forms of cardiovascular diseases (hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM)) and performing drug screen studies. For this purpose, the Snyder lab will collect peripheral blood from 100 HCM patients, 100 DCM patients and 100 control donors. The isolated PBMC will be reprogrammed into iPS cells and used as a shareable resource to broad scientific community for cardiovascular and stem cell research.
The genomic information of these iPSC lines will be obtained by whole genome sequencing. Meanwhile, the iPSCs will be differentiated into cardiomyocytes and treated with different FDA approved cardiac drugs. The drug safety/toxicity will be evaluated and drug response will be deeply analyzed with RNA-seq by comparing the transcriptome before and after the treatment. This study would create an unprecedented opportunity to combine the genomic, transcriptomic and clinical information together to identify differentially expressed genes in HCM and DCM patients, and to determine the different drug response on individual patients.
SETD7 Drives Cardiac Lineage Commitment through Stage-Specific Transcriptional Activation. Lee J et al. Cell Stem Cell. 2018 Mar 1;22(3):428-444.
Molecular and functional resemblance of differentiated cells derived from isogenic human iPSCs and SCNT-derived ESCs.Zhao MT et al. Proc Natl Acad Sci U S A. 2017 Dec 26;114(52):E11111-E11120.
Cell Type-Specific Chromatin Signatures Underline Regulatory DNA Elements in Human Induced Pluripotent Stem Cells and Somatic Cells. Zhao MT et al, Circ Res. 2017 Nov 10;121(11):1237-1250.
Genome-Wide Temporal Profiling of Transcriptome and Open Chromatin of Early Cardiomyocyte Differentiation Derived From hiPSCs and hESCs. Liu Q et al. Circ Res. 2017 Aug 4;121(4):376-391.
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