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Using iPSC-derived Cardiomyocytes to Study the Genetics of Left Ventricular Hypertrophy

May 21, 2012

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Left Ventricular Hypertrophy (LVH) is one of the most potent risk factors for cardiovascular disease (CVD), including ischemic heart disease, chronic heart failure, and particularly CVD death. Cardiac hypertrophy is the response of the myocardium to an increased workload, which usually results from increases in either pressure or blood volume. Numerous lines of evidence suggest that the risk of developing LVH is determined to a significant degree by genetic factors. The overall goal of our research is focused towards identifying novel genes as well as understanding the mechanisms underlying the development of LVH. As a first step, we have performed genome-wide association studies (GWAS) and identified single nucleotide polymorphisms (SNPs) and genes related both to LVH and other important related phenotypes. However these studies only provide statistical evidence which is a common problem related to epidemiologically-based GWAS. Consequently, the next critical step will be to provide a functional annotation and potentially determine the interplay between identified SNPs. Until now, functional studies for LVH have been particularly limited because human primary cardiomyocytes, the key relevant cell type for these phenotypes, were not available for functional analysis. The advent of human iPSC technology provides a novel solution to this problem. We utilize well characterized iPSC derived cardiomyocytes and developed models for LVH. Subsequently, we performed expression analyses to characterize the molecular changes. Novel analysis approaches which combine both expression and GWAS results provide insights into related pathways. Ultimately, this approach can be expanded to other diseases as IPSC derived cell system can be used to recapitulate the disease process, allow for a functional annotation of identified genes, and provide the platform to identify and validate novel drug targets.

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May 21, 2012