SCOR IN PATHOBIOLOGY OF LUNG DEVELOPMENT

该提案结合了基础和临床研究方法， 围产期肺的发育、损伤和修复， 支气管肺发育不良（BPD）和肺动脉高压 新生儿（PPHN），慢性肺疾病（CLD）的主要原因， 婴儿期。 项目1采用糖皮质激素缺乏的小鼠模型 基于促肾上腺皮质激素释放激素（CRH）的靶向缺失 基因 糖皮质激素在正常及发育不良胎肺中的作用 将通过识别类固醇的细胞靶点来分析发展 作用，表征细胞间相互作用和旁分泌的作用 下游信号传导中的因素，并确定肺源性 CRH在肺成熟中起作用。 项目2分析了 细胞表面硫酸乙酰肝素蛋白聚糖，多配体聚糖，它们的脱落 进入细胞外空间，以及它们的诱导剂在修饰细胞外空间中， 参与发育的肝素结合效应物的作用 对伤害的反应。 项目3探讨了肝素- 结合表皮生长因子样生长因子（HB-EGF），一种有效的丝裂原， 肌肉（SM）细胞、成纤维细胞和上皮细胞参与了 肺对损伤的反应。 调节HB-EGF的机制 在正常和异常肺中的合成和生物活性，以及HB-EGF 可能控制异常肺细胞增殖的拮抗剂， 问题研究 项目4和项目5将共同分析 肺用来控制的细胞和分子机制 肺血管SM细胞收缩和生长。 这些反应， 在PPHN的发病过程中，损伤变得失调。 项目4 重点是基因调控缺氧，和相互作用， 内皮源性血管收缩剂和血管舒张剂在大鼠模型中的作用 缺氧诱导的肺重构以及婴儿PPHN。 项目5是基于这样的发现： 响应于这些内皮衍生因子的基质相互作用可 通过改变整合素依赖性调节肺血管SM细胞 信号机制。 这些信号由ECM和可溶性 血管激动剂，可能被整联蛋白拮抗剂阻断， 抑制剂的低氧诱导的肺重建的大鼠模型。 每个项目都将与临床核心密切合作 它将（i）基于对疾病的认识， （ii）提供来自患者的样本和数据 与BPD和PPHN，以及（iii）生成统计分析和研究 的设计. 作为行政核心的项目7将协调这些活动， 跨学科的努力，管理资金和努力的分配 并创建一个SCOR研究社区。 我们的综合搜索方法， 婴儿期CLD的关键问题将促进 新的预防和治疗方法。

This proposal combines basic and clinical research approaches to the development, injury and repair of the perinatal lung that underlie bronchopulmonary dysplasia (BPD) and pulmonary hypertension of the newborn (PPHN), the major causes of chronic lung disease (CLD) of infancy. Project 1 employs a mouse model of glucocorticoid deficiency based on targeted deletion of the corticotrophin-releasing hormone (CRH) gene. The role of glucocorticoids in normal and dysplastic fetal lung development will be analyzed by identifying cellular targets of steroid action, characterizing the role of cell-cell interactions and paracrine factors in downstream signaling, and determining whether lung-derived CRH plays a role in lung maturation. Project 2 analyzes the role of cell surface heparan sulfate proteoglycans, syndecans, their shedding into the extracellular spaces, and their inducers in modifying the action of heparin-binding effectors involved in the developmental response to injury. Project 3 explores the possibility that heparin- binding EGF-like growth factor (HB-EGF), a potent mitogen for smooth muscle (SM) cells, fibroblasts, and epithelial cells, is involved in the response of the lung to injury. Mechanisms that regulate HB-EGF synthesis and bioactivity in normal and abnormal lungs, and HB-EGF antagonists that might control abnormal lung cell proliferation will be studies. Projects 4 and 5 will function in concert to analyze the cellular and molecular mechanisms that the lung uses to control pulmonary vascular SM cell contractility and growth. These responses to injury become deregulated during the pathogenesis of PPHN. Project 4 focuses on gene regulation by hypoxia, and the interaction of endothelial-derived vasoconstrictors and vasodilators in a rat model of hypoxia-induced pulmonary remodeling as well as in infants with PPHN. Project 5 is based on the finding that changes in cell-extracellular matrix interactions in response to these endothelial-derived factors can modulate pulmonary vascular SM cell by altering integrin-dependent signaling mechanisms. These signals, elicited by ECM and soluble vasoagonists, may be blocked by integrin antagonists, possible inhibitors of hypoxia-induced pulmonary remodeling in the rat model. Each project will have a close collaboration with the Clinical Core which will (i) formulate testable clinical hypotheses based on insights from the laboratory studies, (ii) provide samples and data from patients with BPD and PPHN, and (iii) generate statistical analyses and study designs. Project 7, the Administrative Core, will orchestrate these interdisciplinary efforts, manage the distribution of funds and efforts and create a SCOR research community. Our integrated search approach to the critical problem of CLD of infancy will facilitate development of new methods for its prevention and therapy.