Novel Pharmacologic Strategies to Treat Pulmonary Arterial Hypertension (PAH)
Abstract
Pulmonary Arterial Hypertension (PAH) is an incurable, progressive disease characterized by the gradual remodeling of the lung vasculature that has become prevalent in military personnel as well as the African- American population. The sustained increase in pulmonary perfusion pressure and pulmonary vascular resistance imposes extra work on the right side of the heart (right ventricle). Overtime, the right heart becomes hypertrophic and eventually fails leading to high incidence of morbidity and mortality among those afflicted with PAH. Exposure to environmental toxicants, fumes and pollutants, thromboembolic diseases, infection by parasites (e.g. Schistosoma mansoni), and genetic predisposition contribute to the onset and accelerate the evolution of PAH. However, the lack of understanding regarding the specific molecular mechanism(s) that initiate PAH have impeded progress towards a cure. To date, treatment of PAH remains palliative and is focused on the relief of symptoms. The present application, based on the discovery that oxidative stress dysregulates calmodulin kinase II (CaMKII) activity in endothelial cells, tests the focused hypothesis that oxidation of CaMKII promotes uncontrolled endothelial cell proliferation into the lumen of blood vessels ultimately leading to their obliteration and pulmonary vascular disease. It will also be determined whether CAMKII inhibition with known and novel therapeutic compounds can be of utility for the treatment of PAH. Moreover, we propose to develop SMA-011, a novel remedy invented by us that restricts CAMKII pathogenic activation while preserving its physiologic functions. Because of this, it is anticipated that SMA-011 will be effective against PAH while producing minimal undesirable side-effects.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Feb 11, 2016
- Source ID
- W911NF1510410
Entities
People
- Marcelo G. Bonini
Organizations
- Army Contracting Command
- Office of the Secretary of Defense
- University of Illinois at Chicago