Grant: Operating Grant

Chronic pulmonary hypertension is a rare but debilitating and lethal disease characterised by high blood pressure in the lung, causing low oxygen levels in the blood, breathlessness and heart failure. The ability of the heart to compensate for increased workload (and thus provide the body with sufficient blood and oxygen) is the main determinant of survival in this condition. Unfortunately, when compared to adults, efforts to treat chronic pulmonary hypertension in newborns, infants and children are hampered by a rapid and apparently irreversible progression toward end-stage disease and death, despite an expanding range of available treatments. Until more effective treatments are developed, the outlook for children with this condition will remain poor. With the funding received to date, our laboratory has made the important and novel observation that severe chronic pulmonary hypertension is reversible in young animals using drugs that inhibit Rho-kinase (ROCK). In this application, we propose to build upon these observations by targeting ROCK inhibitors to the lung as a means of avoiding effects on other tissues, by further defining the mechanisms by which ROCK inhibition reverses chronic pulmonary hypertension and by exploring the mechanisms behind heart failure in the context of chronic pulmonary hypertension and its therapy. Our ultimate goal is to translate this promising therapy to humans, with the hope of achieving improved outcomes from an otherwise devastating disease.