The aim of this project is to utilize animal models to study hereditary defects in connective tissues. The primary model for these studies is a hereditary fragility and hyperextensibility of cat skin which is transmitted as an autosomal dominant defect. A breeding colony of cats with this defect has been established. Microscopic studies have shown that there are packing defects in dermal collagen in the propositus and his affected offspring. Biochemical analyses will therefore be utilized to identify the basis of this abnormality in collagen fibrillogenesis. Quantitative biochemical analyses of types and relative amounts of collagen polypeptide chains in affected kitten skin will be compared to analyses of both related and unrelated clinically normal cat skin. The collagen chains extracted from both affected and unaffected skin will also be compared to those synthesized by cultured fibroblasts derived from the same animals. The types and amounts of collagen crosslinks in these tissues will be determined. Similar analyses will be carried out on unaffected collagenous tissue in affected animals, and the defect in homozygotes will be compared to that in heterozygotes. If an abnormal molecule can be identified and purified in sufficient quantities, we will attempt to prepare monospecific antisera to identify the cells which are synthesizing the abnormal molecules, and to study the distribution of abnormal molecules in the affected dermis. These analyses will in turn be correlated with physical analyses of the tensile strength and modulus of stress of affected and unaffected skin, and with transmission and scanning electron microscopy analysis of the packing and organization of collagen in fibrils and fibers in the reticular layer of the dermis. These studies should permit us to identify the defect leading to the abnormalities in collagen fibrillogenesis. Since this defect is transmitted as an autosomal dominant trait, this is a unique opportunity to elucidate the pathogenesis of a connective tissue disease that presumably results from a structural gene defect.
NIH ExPorter
NIH ExPorter