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。 该提议重点 肺外基质的主要纤维成分之一，是 弹性纤维，因为它在保持正常状态中至关重要 功能和由于支气管肺的主要特征之一 发育不良（BPD）是依从性和弹性后坐力的丧失。 此外， 关于详细的分子，相对鲜为人知 弹性纤维的特性，特别是微纤维 组成部分，要么与正常肺发育关系和 肺泡化或疾病情况的改变。 也只有 控制矩阵的因素和机制的定义有限 形成。 我们假设存在重大差异，从而 功能受损，存在于分子组成和结构中 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，尤其是糖皮质激素，以及 甲状腺激素在调节弹性纤维中起关键作用 正常肺发育期间的合成和发生的劣质发生 在BPD中。 为了检验这些假设并获得更大的 了解细胞外基质在肺发育中的作用 和疾病进展，我们建议； （1）确定分子 弹性纤维成分表达的成分和时间序列 Ina发育的牛和人肺，（2）确定空间 弹性纤维成分在A的发育中的牛和 人肺，（3）分析胎儿弹性纤维成分的合成 肺植体培养物，并确定一组选择的效果 激素和弹性纤维产生的细胞因子，（4）确定 弹性纤维的组成并表征空间 人类中成分蛋白的分布和合成 发育不良肺。 弹性纤维和分子结构的定义 其合成和组装涉及的机制是必需的 了解疾病的危险并设计有效的干预措施。