The long-term objective of this proposal is to determine the pathogenesis of amyloidosis and its relationship to aging and nutrition. We are postulating that the administration of casein or azocasein to amyloid susceptible mice overwhelms the proteolytic capacity of the mononuclear phagocytic system (MPS), either by inhibition of specific cell membrane associated enzymes or by activation of serine esterase inhibitors, one of which may be SAP or amyloid P component. The influence of strain, age and gender of the mouse on the incidence of amyloidosis is presumably reflected in reduced MPS protease activity which in turn can be modified by altering dietary factors, particularly and type of fat (saturated and unsaturated, omega 3 and omega 6 fatty acids) and the level of antioxidants (vitamin E). Using two models of experimental amyloidosis, i.e., 1) an acute model in which young CBA/J (susceptible) and A/J (resistant) received daily azocasein injections and 2) a chronic model in which aged C57B1/6Nia, A/J, and SJL/J mice are maintained on high casein diets, our specific aims are: first, to determine whether strain differences in susceptibility to amyloidosis are related to the ability of the MPS to degrade serum amyloid A (SAA) precursor protein or to differences in MPS production of prostaglandins or activated oxygen radicals; second, to determine if observed differences in ability of the MPS to degrade SAA can be explained by the presence of competitive substrates such as casein or by enzyme inhibitors such as SAP; third, to determine whether altering dietary factors such as the type of fatty acid and level of antioxidants can alter the incidence and severity of amyloidosis in the two models and whether such changes can be correlated with changes in MPS protease activity. The effect of dietary manipulations prior to the induction of experimental amyloidosis as well as after amyloidosis is clearly established will be studied. To achieve these aims we will utilize cell cultures of peritoneal macrophages and Kupffer cells from animals that have been maintained on different dietary and amyloid inducing protocols and compare proteolytic activity, prostaglandin profiles and production and metabolism of activated oxygen radicals. These studies should provide helpful information to aid in designing rational dietary or therapeutic regimens for intervention in the development or for the treatment of human amyloidosis.
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