Grant: Operating Grant

Sex differentiation, in addition to being responsible for the obvious differences between males and females, also has consequences on general health. In particular, cardiovascular diseases affect women and men differently. In addition to sex steroids (mostly estrogens in females and testosterone in males), there is now evidence that genes present on sex chromosomes (including the male-specific chromosome Y) also play critical roles. However, little is known about the functions of chromosome Y genes besides their effects on male reproductive organs, and there is almost no information explaining how they might affect cardiovascular health. We have obtained evidence that genetic variants of chromosome Y are responsible for differences in the size and contractile properties of cardiac cells from different mouse strains. Preliminary experiments have revealed that these effects are complex, as chromosome Y variants transform the manner in which several cardiac genes respond to testosterone, in part by programming around the time of birth how cardiac cells will respond to testosterone later during adult life. We have therefore designed experiments aimed at elucidating how chromosome Y could affect the characteristics of cardiac cells and their responsiveness to testosterone, and identify the mechanisms responsible for these effects.