Mechanisms of Vascular Injury in the preterm lung

描述(由申请人提供)： 这项建议描述了一个5年计划，以促进学术生涯的发展，成为一名独立的调查员。这项提案的首席研究员已经完成了新生儿-围产期医学的研究，目前是该分部的全职教员。这项研究的重点是研究产前炎症抑制血管和肺泡发育的机制，产前炎症与早产和支气管肺发育不良密切相关。该计划将加强对发育中胎儿的肺发育和血管生物学机制的理解。 血管发育和肺泡发育受到抑制的早产儿支气管肺发育不良和早产动物模型的慢性肺损伤的机械通气和暴露于氧气。该实验室先前已经表明，暴露于产前炎症的早产羔羊抑制了肺泡化。这一建议验证了IP-10(一种干扰素诱导的CXC趋化因子)的诱导和IEP-10受体CXCR3的激活是产前炎症导致早产儿肺血管和肺泡发育抑制的关键介质的假说。羊肉。目的：1)确定羊膜腔内注射内毒素诱导早产羔羊血管发育受阻的最佳时机；2)研究重组绵羊IP-10宫内气管内注射对血管和肺泡发育的影响；3)通过抑制其受体CXCR3，阻断孕期EP-10信号转导通路，抑制产前炎症诱导的肺损伤反应。 研究工作将在乔布博士和共同导师的监督下进行，他们都是肺部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分部为开展拟议的研究计划提供了理想的环境，因为有一批有才华的研究人员拥有丰富的资源和广泛的专业知识。这项建议中的实验设计包含了具有挑战性的但特别是在这种环境下可实现的目标，这些目标将为支气管肺发育不良的发病机制提供重要的知识。

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.