SYNDECANS IN MODELS OF BRONCHOPULMONARY DYSPLASIA

支气管肺发育不良模型中的 SYNDECAN

• 批准号: 6184705
• 负责人: MERTON R BERNFIELD
• 金额: $ 25.47万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6184705
• 关键词: baboons; bronchopulmonary dysplasia; disease /disorder model; embryo /fetus cell /tissue; embryo /fetus tissue /cell culture; gene deletion mutation; genetically modified animals; histopathology; laboratory mouse; lung injury; membrane proteins; model design /development; oxygen tension; premature infant animal; respirators; syndecan

A major aspect of the pathogenesis of BPD in newborns is the inflammatory response to injury caused by mechanical ventilation at high FiO2. Ventilated fetal baboons develop the pathophysiological, histologic and biochemical features of the infant with BPD, and provide an opportunity to test hypothesis for the pathogenesis of BPD and to evaluate preventative and therapeutic measures. We study the cell surface heparan sulfate proteoglycans (HSPGs) known as the syndecans. These single membrane spanning protein contain extracellular domains (ectodomains) that bear HS chains near the N- termini, distant from the plasma membrane. Syndecans are on the surface of every adherent cell where they act as co-receptors for a variety of growth factors, cytokines, chemokines and cell adhesion molecules, as well as coordinate, in part, the highly complex reparative response to tissue injury. Specifically, syndecan-1 and -4 are induced in response to tissue injury, agents produced during tissue injury cause syndecan ectodomains to be released intact from cell surfaces, yielding soluble effectors that modify the activities of wide variety of proteins and act as dominant negative inhibitors. Mice containing a targeted deletion of the syndecan-1 gene and mice that transgenically over-express syndecan-1 under the broadly acting CMV promoter show major defects in wound repair: the null mice show slow epithelial response to injury and the over-expressing mice shed excessive amounts of the soluble syndecan-1 ectodomains, causing a major disturbance in repair of injury. We hypothesize that the persistent injury of the lung by mechanical ventilation at high FiO2 leads to excessive shedding of the soluble syndecan ectodomains, that the biological activities of these PGs delay the reparative response and contribute to the changes recognized pathologically and clinically as BPD, and reducing the level of these ectodomains will ameliorate, in part, the progression to BPD. Specifically, we aim to (i) to correlate syndecan expression and shedding with histopathological changes in ventilated pre-term baboon lungs; (ii) determine the biological activities of the soluble ectodomains from ventilated lungs; (iii) establish baboon lung cultures to investigate mechanisms of syndecan induction and shedding and to produce syndecan ectodomains; (iv) assess whether the soluble ectodomains are casually related to development of BPD in the baboon models.

新生儿BPD发病机制的一个主要方面是高氧氧下机械通气损伤引起的炎症反应。通风胎狒狒发育了BPD婴儿的病理生理、组织学和生化特征，为BPD的发病机制假说的检验和预防和治疗措施的评估提供了机会。我们研究了被称为syndecans的细胞表面硫酸肝素蛋白聚糖（HSPGs）。这些单膜跨越蛋白含有细胞外结构域（外结构域），其在远离质膜的N端附近携带HS链。Syndecans存在于每个粘附细胞的表面，在那里它们作为多种生长因子、细胞因子、趋化因子和细胞粘附分子的共受体，并在一定程度上协调对组织损伤的高度复杂的修复反应。具体来说，syndecan-1和-4在组织损伤时被诱导，组织损伤过程中产生的药物导致syndecan外结构域完整地从细胞表面释放，产生可溶性效应物，这些效应物可以改变多种蛋白质的活性，并作为主要的负抑制剂。含有syndecan-1基因靶向缺失的小鼠和在广泛作用的巨细胞病毒启动子下转基因过表达syndecan-1的小鼠在伤口修复中表现出主要缺陷：缺失小鼠对损伤的上皮反应缓慢，过表达小鼠脱落了过量的可溶性syndecan-1外结构域，导致损伤修复的主要障碍。我们假设，在高FiO2条件下，机械通气对肺的持续损伤导致可溶性syndecan外结构域的过度脱落，这些PGs的生物活性延迟了修复反应，并导致了病理和临床公认的BPD变化，降低这些外结构域的水平将在一定程度上改善BPD的进展。具体来说，我们的目标是(i)将通气的早产儿狒狒肺部的syndecan表达和脱落与组织病理学变化联系起来；（ii）测定通气肺中可溶性外结构域的生物活性；（iii）建立狒狒肺培养，研究syndecan诱导和脱落的机制，并产生syndecan外结构域；（iv）评估可溶外结构域是否与狒狒模型中BPD的发展偶然相关。