Mechanisms of Vascular Injury in the preterm lung

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DESCRIPTION (provided by applicant): This proposal describes a 5 year program for fostering development of an academic career to an independent investigator. The principal investigator for this proposal has completed fellowship in Neonatal-Perinatal medicine and is currently a full time faculty member of the division. The focus of the research is on studying the mechanisms of inhibition of vascular and alveolar development caused by antenatal inflamation which is strongly associated with preterm births and bronchopulmonary dysplasia. The program will enhance the understanding of mechanisms of lung development and vascular biology in the developing fetus. Vascular development and alveolar development are inhibited in preterm infants with bronchopulmonary dysplasia and in preterm animal models of chronic lung injury induced by mechanical ventilation and exposure to oxygen. This laboratory has previously shown that preterm lambs exposed to antenatal inflammation have inhibited alveolarization. This proposal tests the hypothesis that induction of IP-10 (a y-interferon inducible CXC chemokine) and activation of IEP-10 receptor CXCR3 are critical mediators of antenatal inflammation induced inhibition of pulmonary vascular and alveolar development in the preterm. lamb. The specific aims include 1) To establish the optimum time of injection of intraamniotic endotoxin to induce inhibited vascular development in preterm lamb 2) To study the effects of in utero intra-tracheal infusion of recombinant sheep IP-10 on vascular and alveolar development and 3) To inhibit antenatal inflammation induced lung injury response by blocking antenatal EP-10 signaling via inhibition of its receptor CXCR3. The research work will be conducted under the supervision of Dr. Jobe and co-mentors who are all recognized experts in different aspects of pulmonary biology. The Children's Hospital Research Foundation and the Division of Pulmonary Biology provides an ideal setting in which to conduct the proposed research program because of the abundant resources and wide ranging expertise of a talented group of investigators. The experimental design in this proposal incorporates challenging but, particularly in this environment achievable goals that will provide important knowledge in the pathogenesis of bronchopulmonary dysplasia.