This application seeks five year funding for the K-23 Award: Patient-Oriented Research Career Development. The principal investigator, Ikechukwu I. Ekekezie, M.D., is currently Assistant Professor of Pediatrics, University of Missouri-Kansas City School of Medicine, Attending Neonatologist, Children's Mercy Hospital, Kansas City. The mentor for this proposal is William E. Truog, M.D., Professor of Pediatrics, University of Missouri Kansas City School of Medicine. The overall objective of this proposal is to provide the necessary support for the evolution of Dr. Ekekezie's career from that of a new productive investigator into an independent physician scientist investigating pathogenesis and treatment of chronic lung disease of prematurity. The application brings together three elements: 1) an able and active clinician-candidate for research career development (Dr. Ekekezie); 2) a superb physical and intellectual environment for clinical and applied research; and 3) the most common, but poorly understood, neonatal pulmonary disorder remaining: chronic lung disease of prematurity (CLD). The improvement in mortality afforded by prenatal corticosteroid and by post-natal surfactant therapy has increased the prevalence of CLD. No current therapy, such as anti-elastase or antioxidant therapy, appears to reduce significantly the severity of CLD. Comprehensive understanding of its pathobiology is lacking. Dr. Ekekezie is currently investigating the use of inhaled nitric oxide to ameliorate CLD. He has a supplement to R-01 HL58125, which has funded his studies examining inflammation and matrix injury in CLD. He has helped design a complex clinical trial as a proposed Co-Investigator for a trial currently under review (R-01 HL62514). He has developed expertise in the biology of extracellular matrix proteins including laminin, and in pro-inflammatory cytokines and their contribution to the evolution of CLD. The clinical study proposed for this application is to examine the disruption of the basement membrane and extracellular matrix by metalloproteinases (MMPs) in CLD and to examine the effects of nitric oxide and corticosteroid therapy on MMP activity in CLD. Therapy with anti-MMP agents may then be studied. Appropriate use of potential new therapies will necessitate evaluation of timing, dosage, side effects, and interactions with concomitant therapies. The often unhappy history of therapeutics in neonatology demands that the most critical thinkers available use their skills in the application of new treatments to sick newborn infants. The investment in Dr. Ekekezie represented by this Award - coupled with his own enthusiasm, skills, intelligence, and high oral standards -- ought to result in his being propelled into the next generation leadership group in this area. The K-23 Award mechanism is an ideal way to advance him from here to there.
