The long-term objective of this research is to investigate the function of a newly discovered mitochondrial progesterone receptor, PR-M. We believe that progesterone acts via this receptor to increase cellular ATP production in multiple tissues to meet the increased metabolic demands of pregnancy. Cardiac function dramatically changes with pregnancy with increased heart rate and contractility requiring increased ATP production. Inadequate cardiac adaptation may contribute to placental insufficiency related to preeclampsia and intrauterine growth restriction.
Our aim i s to investigate the hypothesis that PR-M increases cellular respiration in the heart. To test this hypothesis we will temporally express human PR-M in the mouse heart using a heavy myosin polypeptide 6 promoter in a Tetracycline-On (Tet-On) system. Tissue and temporal expression of the transgene will be determined by realtime RT-PCR and western blot analysis. Cardiac function in transgenic animals will be evaluated during late gestation and in non- pregnant models of cardiac hypertrophy to mimic volume and pressure overload. Assays will include echocardiography, heart morphometry, microscopic analysis of capillary density, fibrosis and apoptosis and determination of tissue ATP levels. Transgenic overexpression is a valuable tool to analyze the tissue function of PR-M. We believe that enhanced ATP production secondary to PR-M expression will diminish cardiac hypertrophy secondary to volume and pressure overload in the study models. These studies will further develop a novel mechanism in which progesterone modulates cellular respiration via a direct affect on the mitochondria. Additionally, the created PR-M transgenic mouse can be cross-bred with other tissue specific Tet-On strains for future studies of PR-M function in the mammary gland, liver, skeletal muscle, adipose and brain. PUBLIC HEALTH STATEMENT Pregnancy is associated with dramatic changes in a woman's body including a great increase in the workload of the heart. This process requires an increase in ATP which serves as the major fuel source for the cell. Our studies are investigating a new receptor for the reproductive hormone, progesterone, located in the mitochondria of the cell where ATP is produced. We believe that this receptor provides a mechanism whereby progesterone increases cellular ATP formation to meet the many metabolic demands of pregnancy. Dysfunction of this system could contribute to pregnancy related diseases.