Genetics of Directed Embryonic Stem Cell Differentiation

DESCRIPTION (provided by applicant): Repair of the damaged heart using cardiomyocytes derived from embryonic stem cells is a promising avenue for treatment of heart disease. Many fundamental questions about stem cell differentiation and cardiomyoplasty mus t be answered before that promise is realized in the clinic. We propose to develop a broadly applicable, cell based system to identify genetic factors involved in the directed differentiation of ES cells to cardiomyocytes. In Phase I we will determine the feasibility of this system by establishing a panel of ES cell lines from F2 embryos of one strain-pair, measuring the extent of differentiation to cardiomyocytes under defined culture conditions, and conducting a statistical analysis for quantitative trait loci (QTL) for differentiation to cardiomyocytes. The aim of Phase I is to demonstrate that the proposed ES cell panel can identify subchromosomal regions of the genome harboring one or more genes involved in differentiation of ES cells. In Phase II, F2 E S lines from additional strain-pairs will be established and, in conjunction with a panel of F1 ES cells, used to screen for genetic determinants of directed differentiation under a variety of culture conditions. The platform will be commercialized through strategic alliances with pharmaceutical and biotech companies, as well as in collaborations with academic institutions. PUBLIC HEALTH RELEVANCE: Over 13 million Americans are afflicted with coronary heart disease each year, leading to half a million death s and healthcare costs in excess of fifty billion dollars. Using stem cells to repair the damaged heart is a promising new approach to treat a disease with very few treatment options. This project will aid in this approach by building a genetic system to i dentify the factors that influence production of heart cells from embryonic stem cells.