Grant: Operating Grant

The morbidity and the mortality related to respiratory disordered in newborn and during infancy are more observed in males than females. The underlying mechanisms of such sex-specific differences are still un-determined. Interestingly, we found that erythropoietin (Epo) prevents respiratory depression in newborn mice, and that this effect is more important in male than female mice. Originally, Epo was discovered as a hormone able to increase the production of red blood cells (such occurring in anemia or doping). Now we know that Epo is also synthesized in neuronal tissue (cerebral Epo) and exert in brain crucial protective function upon conditions of poor oxygen availability (hypoxia). Brainstem is the region located in the posterior part of the brain that holds the major centers associated with control of respiration. In newborn mammals the respiratory control system in the brainstem is in full process of maturation and development, thus hypoxia-induced respiratory depression is more important than in adult animals. Hence, developing strategies allowing the respiratory control system to maintain adequate and efficient breathing responses to hypoxia would be a significant breakout in the development of new clinical interventions and biomedical sciences. Based on our exciting findings, we propose to that testosterone (the hormone that promotes the "masculinization" of the male brain around birth) interacts with Epo in the regulation of respiration in newborn mice. We will define: the sex specific expression of Epo and its receptors in the brainstem; the sex-dependent respiratory depression in absence (inactivation) of cerebral Epo; and whether the testosterone suppression (castration) or metabolization abolishes the impact of Epo on respiratory depression. These measurements will be performed in conditions of both normal and limited oxygen availability, thus mimicking conditions of respiratory diseases. The potential health and social benefits are very significant.