One current focus is elucidating the developmental functions of peroxisome proliferator activated receptor gamma (PPARγ) in embryonic, placental and maternal development of the vascular system. As part of a long standing collaboration with Dr. Richard Mortensen at the University or Michigan we are determining the consequences of genetic loss-of-function in vivo and in vitro using a combination of developmental biologic approaches including chimera analysis and conditional gene inactivation, or mosaic analysis. Current results indicate that PPARγ is required for embryonic survival because it performs functions critical for vascular development of at least two placental trophoblast compartments. PPARγ is also expressed and may perform analogous functions in human placental trophoblast suggesting that using currently available pharmacologic agents to manipulate PPARγ activity may alter the outcome of human pregnancy. Therefore, we are also studying the effects of PPARγ pharmacologic agonists on murine pregnancy focusing on trohpoblast differentiation, placental and embryonic development and the possibility of teratogenic effects.
Collaborative experiments with Dr. Bruce Spiegelman's laboratory used chimera methodology to confirm in vivo and in vitro the hypothesis that PPARγ is required for adipocyte differentiation. Analogous collaborative experiments with Dr. Mason Freeman's laboratory established that PPARγ is not required for macrophage differentiation. However, macrophage lacking PPARγ show several abnormalities in lipid metabolism with implications for atherosclerosis and other inflammatory diseases.