The objective of this proposal is to discover the pathogenesis of amyloidosis in man and in the mouse model of the disease, so that we devise new approaches to the prevention and treatment of patients with this fatal condition. Current evidence suggests that secondary amyloidosis results from diseases which cause accelerated synthesis and the incomplete catabolism of a circulating precursor, serum amyloid A protein (SAA), which is then deposited extracellularly as amyloid A fibrils. It is proposed to investigate whether one or more of the 6 isotypes of SAA is the predominant precursor for AA fibrils. Using our monoclonal antibodies to SAA, we will investigate the binding of SAA to leukocyte membranes and whether patients with amyloidosis have an SAA receptor defect or SAA processing abnormality. The latter may be due to an inherited or acquired enzyme deficiency or due to increased production of a protease inhibitor. Amyloid fibrils are remarkably insoluble in vivo and we will investigate whether the resistance to proteolytic digestion is due to the close association of the fibrils with amyloid P component (AP), which has recently been found to be an inhibitor of elastase. Using an in vitro culture system, it is proposed to investigate the hypothesis that Kupffer cells regulate the hepatocyte synthesis of SAA and perhaps other acute phase proteins by local production of the 15,000 MW Interleukin 1 (equal leukocytic pyrogen). Further studies will investigate whether the specificity of the hepatocyte response to IL1 in making a whole range of acute phase proteins is modulated by steroid hormones. The role of prostaglandins and cyclic nucleotides in inhibition of SAA synthesis will be assessed. The half life and fate of the SAA isotypes will be studied in human volunteers infused with radiolabelled SAA, both under baseline conditions and during an acute phase response, induced by the pyrogenic steroid etiocholanolone. Our goal is to predict those patients at risk of developing amyloidosis and to dissect the pathway of SAA metabolism so as to target therapy more effectively in patients with secondary amyloidosis. During studies of SAA biosynthesis, basis mechanisms controlling synthesis of plasma proteins by the liver will be illuminated and insight will be gained into the function of SAA, whose concentration rises so dramatically after acute phase stimuli.
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