Genetics of Directed Embryonic Stem Cell Differentiation

描述（由申请人提供）：利用胚胎干细胞衍生的心肌细胞修复受损的心脏是治疗心脏病的一个有前途的途径。干细胞分化和心肌成形术的许多基本问题必须得到回答，才能在临床上实现这一希望。我们建议开发一种广泛适用的、基于细胞的系统来识别参与胚胎干细胞向心肌细胞定向分化的遗传因素。在I期，我们将通过建立一组来自一个菌株对的F2胚胎的ES细胞系，测量在规定的培养条件下向心肌细胞分化的程度，并对向心肌细胞分化的数量性状位点（QTL）进行统计分析，来确定该系统的可行性。第一阶段的目的是证明所提出的胚胎干细胞组可以识别基因组的亚染色体区域，其中包含一个或多个参与胚胎干细胞分化的基因。在第二阶段，将建立来自其他菌株对的F2 ES系，并与F1 ES细胞面板一起，用于筛选在各种培养条件下定向分化的遗传决定因素。该平台将通过与制药和生物技术公司的战略联盟以及与学术机构的合作实现商业化。公共卫生相关性：每年有超过1300万美国人患有冠心病，导致50万人死亡，医疗费用超过500亿美元。利用干细胞修复受损的心脏是一种很有前途的新方法，可以治疗一种治疗方法很少的疾病。这个项目将通过建立一个遗传系统来确定影响胚胎干细胞产生心脏细胞的因素，从而帮助实现这一方法。

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 must 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 ES 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 deaths 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 identify the factors that influence production of heart cells from embryonic stem cells.