Grant: CIHR Fellowship

Congenital central hypoventilation syndrome (CCHS) is a respiratory disease that few people have heard about. Yet, it is among the most serious and often fatal diseases that a person can be born with. Due to a mutation in a single gene (called Phox2b), a sub-set of brainstem neurons that normally control breathing do not function properly. As a result, CCHS patients repeatedly "forget to breathe," and depend on mechanical ventilation for survival. Mechanical ventilation is invasive and unreliable: many deaths have resulted simply from equipment failure. As Henry Winkler, celebrity spokesperson of the CCHS Foundation, points out: "it only takes a second." CCHS is an orphan disease: we understand little about the role gene mutations play in causing it. Consequently, CCHS has no cure and no drugs have been developed to treat it. Remarkably, a serendipitous discovery made a decade ago found that female CCHS patients using a contraceptive drug containing a potent progesterone drug started breathing normally. How progesterone restored breathing in these patients has never been determined. Our objectives are to utilize a rodent model to discover the role that PHOX2B plays in control of breathing, and determine how progesterone can 'rescue' breathing. By using a custom virus, we will selectively manipulate the survival and function of brainstem neurons that normally express PHOX2B. These interventions do not harm the rodents, but produce respiratory deficits similar to CCHS patients. We can use these deficits to interrogate the pathogenesis of the disease, and the potential therapeutic effects of progesterone. By providing fundamental insights into breathing control and CCHS, we aim to provide a foundation for the development of new treatments so that patients rely less on mechanical ventilation, improving life-expectancy and quality-of-life. Discovering how progesterone affects breathing also has implications for the health of women who use contraceptive drugs daily.