This grant is a competitive renewal of HL-15965 (Elastin Metabolism).
Its specific aims are: 1) to study the expression and processing of elastin precursors during lung and aorta development, 2) to identify factors important to elastin deposition in normal and diseased lung and aorta; and 3) to clarify linkages between the crosslinking of elastin and steps important to elastin synthesis, degradation and turnover. In this regard, studies on the regulation of lysyl oxidase and its relationship to elastin deposition are included. By examining elastin and lysyl oxidase expression, we hope to clarify further several relationships important to elastin metabolism and elastin-related diseases. For example, we will address questions related to the relative importance of cross- linking to elastin deposition in perinatal lung and aorta, particularly during periods when elastin undergoes rapid synthesis. Further, proteinase instillation into the lung of adult animals effects rapid deposition of new elastin. We will examine this response as a means of assessing to what extent, the expression of tropoelastin isoforms is altered in developmental versus disease models. It is the hope that subsequent findings will be useful in better defining concepts important to understanding elastin's role in normal development and in pulmonary and arterial diseases. The methods will involve immunological, biochemical and molecular biology techniques in studies utilizing rodents or tissue explants from rodents or young chicks. Elastin mRNA activity and expression will be examined using cDNA probes derived from elastin gene fragments. The nature of translated products will be assessed in cell-free translation systems. In addition, lysyl oxidase will be studied by using antibodies to lysyl oxidase, improved methods for detecting and isolating lysyl oxidase, and eventually molecular probes.
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