In designing this proposal equally careful attention has been placed on the research plan and the mentoring component. The research plan is based upon a patient-oriented approach to primary pulmonary hypertension (PPH), a fatal disease characterized by progressive increase in pulmonary artery pressure. Our data show that NO and NO reaction products (NOx) are lower in lungs of PPH than health controls. We propose that the low levels of NO and NOx in PPH are due to decreased NO synthesis and increased NO consumption by reactions with oxidant species leading to alternative reaction endproducts. Preliminary studies indicate that NOx are correlated in an inverse relationship to pulmonary artery pressures in PPH. Theoretical modeling and simulation of our data suggest that progression and mortality in PPH is predicted by NOx. These data indicate a role for NO and oxidants in the pathophysiology of PPH. To test our hypothesis that NOx predict progression of PPH, we will obtain longitudinal data on pulmonary artery pressures, cardiac output and lung diffusion capacity in PPH patients, and model these factors as linear functions of the corresponding levels of NOx. To test our hypotheses on mechanisms responsible for low NO levels, NO synthase (NOS) levels and activity will be quantitated and localized in PPH lungs in comparison to controls. Further, oxidative mechanisms of NO consumption will be studied in vivo and in an in vitro cell culture system. The program will allow the candidate to focus intensively on patient-oriented research and expand her mentoring endeavors of beginning clinician investigators. The mentoring component of this proposal includes instruction in molecular biology, analytic techniques, research design, data interpretation, preparation of abstracts, manuscripts, and presentations taught by the candidate, with input from biostatistician, and on a quarterly basis from advisors who are highly successful in patient-oriented research. Since clinical research increasingly utilizes basic investigative techniques, knowledge of basic research is incorporated into the program through formal graduate level coursework. The program will result in the development of physician-scientists that use state-of-the art research techniques for investigation of human disease.
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