MOLECULAR ANALYSIS OF DEVELOPING LUNG EXTRACELLULAR MATRIX

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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.