Mechanisms of Vascular Injury in the preterm lung

描述（由申请人提供）： 该提案描述了一个为期5年的计划，以促进学术生涯的发展，以独立的调查。 该提案的主要研究者已完成新生儿-围产期医学研究金，目前是该部门的全职教职员工。 研究的重点是研究与早产和支气管肺发育不良密切相关的产前炎症抑制血管和肺泡发育的机制。 该计划将加强对发育中胎儿肺发育和血管生物学机制的理解。 在支气管肺发育不良早产儿和机械通气和暴露于氧气诱导的慢性肺损伤早产动物模型中，血管发育和肺泡发育受到抑制。 本实验室先前已表明，早产羔羊暴露于产前炎症抑制肺泡化。 该提议检验了IP-10（γ-干扰素诱导型CXC趋化因子）的诱导和IEP-10受体CXCR 3的激活是早产儿中产前炎症诱导的肺血管和肺泡发育抑制的关键介质的假设。lamb. 具体目的包括：1）建立羊膜内注射内毒素诱导早产羔羊血管发育受抑制的最佳时间; 2）研究子宫内气管内输注重组绵羊IP-10对血管和肺泡发育的影响; 3）通过抑制其受体CXCR 3阻断产前EP-10信号传导来抑制产前炎症诱导的肺损伤反应。 研究工作将在Jobe博士和共同导师的监督下进行，他们都是肺生物学不同方面的公认专家。 儿童医院研究基金会和肺生物学部提供了一个理想的环境，在其中进行拟议的研究计划，因为丰富的资源和广泛的专业知识的一组有才华的研究人员。 本提案中的实验设计具有挑战性，但特别是在这种环境下可实现的目标，这将提供重要的知识，支气管肺发育不良的发病机制。

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.