Grant: Project Grant

Progesterone (a female sex hormone) has been implicated in the potentiation of breathing during pregnancy and specific phases of the menstrual cycle in women. Additionally, the reduction in circulating progesterone levels in women is proposed to be a main contributing factor to the increased frequency of sleep disordered breathing in menopause, although the mechanisms through which progesterone affects breathing are not yet fully understood. In this project we will investigate the mechanisms underlying sex-hormone induced changes in gene expression and ventilation in control rats and in a rat model of central hypoventilation, a condition in which altered development and/or function of brain areas that sense changes in blood gases causes inability to properly respond to gas stimuli. We will test the respiratory effects and assess changes in gene expression following treatment with a potent synthetic sex hormone (etonogestrel), a drug that induced partial recovery of respiration in a hypoventilation disorder, congenital central hypoventilation syndrome (CCHS). Because the role in respiratory control of PHOX2B and the mutated form of PHOX2B that causes CCHS is not fully understood, we will also investigate their function in vivo by changing their expression level in selected respiratory control areas of the brain. We will then assess changes in respiratory function and in gene and protein expression caused by these manipulations. Results from our experiments will explore key aspects of respiratory control and chemoreflex modulation induced by sex hormones and the transcription factor PHOX2B.