Funding outcome

Progesterone (a female sex hormone) has been implicated in the potentiation of breathing during pregnancy and during 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 following menopause. In this project we will investigate the mechanisms underlying sex-hormone induced ventilatory recovery in a model of central hypoventilation, a condition in which an impaired response to respiratory challenges (high CO2 or low O2 levels of inspired air) occurs because of altered development and/or function of a key area of the brain that senses changes in CO2 and pH levels. We will use a female rodent model to generate a impairment in CO2 detection and we will provide a long-term treatment with a synthetic progestin drug (Etonogestrel) that has been previously proposed to induce partial recovery of respiratory function in a form of chronic hypoventilation, congenital central hypoventilation (CCHS) patients. We will test recovery of respiratory function in this model and will analyze brain tissue to assess the areas in the brain that are responsible for this recovery and the cellular and molecular changes associated with the hormonal treatment. We will also investigate the function of the gene affected in CCHS (i.e., PHOX2B): we will reduce expression of the naive protein and we will ectopically express the mutated PHOX2B protein in the area of the brain that detects CO2 changes. We will assess changes in respiratory function and in gene and protein expression caused by these manipulations. Results from our experiments will explore some important aspects of the mechanism of action of sex hormones that promote chemoreflex recovery, and will contribute to reveal key molecular mechanisms associated with the pathogenesis of CCHS and other central hypoventilation syndromes.