MOLECULAR ANALYSIS OF DEVELOPING LUNG EXTRACELLULAR MATRIX

发育中肺细胞外基质的分子分析

• 批准号: 6202520
• 负责人: JOEL ROSENBLOOM
• 金额: $ 21.19万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6202520
• 关键词: age difference; animal tissue; bronchopulmonary dysplasia; elasticity; extracellular matrix; histogenesis; human fetus tissue; human tissue; immunocytochemistry; in situ hybridization; lung; molecular pathology; protein biosynthesis; tissue /cell culture

The ability of the lung to carry out normal air exchange is dependent upon the integrity of a complex extracellular matrix. This proposal focuses on one of the major fibrous components of the lung extracellular matrix, the elastic fiber, because of its central importance in maintaining normal function and because one of the cardinal features of bronchopulmonary dysplasia (BPD) is a loss of compliance and elastic recoil. Furthermore, relatively little is known concerning the detailed molecular characteristics of the elastic fiber, particularly the microfibrillar component, either in relationship to normal lung development and alveolarization or alterations in disease situations. There also is only limited definition of factors and mechanisms which control matrix formation. We hypothesize that significant differences, resulting in impaired function, exist in the molecular composition and architecture of the matrix between the normal and dysplastic lung. We further hypothesize that several hormones and cytokines, particularly glucocorticoids and thyroid hormone play critical roles in the regulation of elastic fiber synthesis during normal lung development and int he aberrancies occurring in BPD. In order to test these hypotheses and to obtain a greater understanding of the role of the extracellular matrix in lung development and disease progression, we propose to; (1) determine the molecular composition and temporal sequence of expression of elastic fiber components ina the developing bovine and human lung, (2) determine the spatial distribution of elastic fiber components in athe developing bovine and human lung, (3) analyze the synthesis of elastic fiber components in fetal lung explant cultures and to determine the effects of a select group of hormones and cytokines on elastic fiber production, (4) determine the composition of the elastic fiber and to characterize the spatial distribution and synthesis of the component proteins in the human dysplastic lung. Definition of the molecular structure of the elastic fiber and the mechanisms involved in its synthesis and assembly are requisite to understanding disease derangements and devising effective interventions.

肺进行正常空气交换的能力取决于 复杂的细胞外基质的完整性。这项提案的重点是 肺细胞外基质的主要纤维成分之一， 弹性纤维，因为它在维持正常状态中起着核心作用 功能和因为支气管肺的主要特征之一 发育不良(BPD)是一种顺应性和弹性反冲的丧失。此外， 关于详细的分子，我们知之甚少。 弹性纤维的特性，特别是微细纤维 成分，无论是与正常的肺发育和 肺泡化或在疾病情况下的改变。还有就是只有 对控制矩阵的因素和机制的有限定义 队形。我们假设显著的差异，导致 功能受损，存在于分子组成和结构中 介于正常肺和发育不良肺之间的基质。我们进一步假设 几种激素和细胞因子，特别是糖皮质激素和 甲状腺激素在弹性纤维调节中的关键作用 肺正常发育过程中的合成及其异常发生 以BPD为单位。为了检验这些假说并获得更大的 细胞外基质在肺发育中的作用 和疾病的进展，我们建议：(1)确定分子 弹性纤维成分的组成和表达的时间顺序 在发育中的牛和人的肺中，(2)确定空间 弹性纤维成分在发育中的牛和牛中的分布 人肺，(3)分析胎儿肺组织弹性纤维成分的合成 肺外植体培养，并确定一组精选的 激素和细胞因子对弹性纤维产生的影响，(4)决定 弹性纤维的组成和空间的表征 组成蛋白在人体内的分布和合成 发育不良的肺。 弹性纤维的分子结构的定义和 参与其合成和组装的机制是必要的 了解疾病错乱并制定有效的干预措施。