Amyloidosis comprises a group of disorders characterized by the extracellular accumulation of protein fibrils. The distribution of such fibrils in subendothelial locations of affected organs and vessels can lead to the eventual impairment of vital organ functions. Analysis of the major polypeptide constituents of amyloid deposits reveals distinct classes derived from normal plasma constituents. Serum amyloid A (apoSAA) is a unique family of plasma HDL apoproteins that are precursors of the amyloid A fibril protein of AA type amyloidosis. Nothing is known about the function(s) of the apoSAA's and little is known concerning their role in the development of amyloidosis. The major aims of this project are 1) to elucidate the function(s) of the SAA apoprotein family, 2) to investigate the mechanisms of the pathogenesis of the AA variety of amyloidosis and 3) to ask whether and, if so, in what ways the principles underlying amyloidogenesis of the AA type are relevant to other types of amyloidosis. The mouse model system will be used to continue our investigations. We will identify the cell types responsible for synthesis of SAA1, SAA2 and SAA3 mRNA. We will identify the SAA3 apoprotein and examine the tissue interactions and fate of the three SAA apoproteins. Fibroblasts, macrophages, endothelial cells, smooth muscle cells, and adrenal gland will be examined for the presence of apoSAA HDL-specific receptors. If the apoSAA HDL receptor is identified, we will ascertain whether it is distinct from the HDL receptor, whether it is regulated in response to injury or inflammatory conditions, what cell types possess it, and whether its levels are elevated in amyloidotic tissues. The possibility that SAA alters cholesterol transport activities of HDL will be tested. The role of apoSAA-HDL interaction with cells or matrix components will be explored in regard to pathogenesis of AA type amyloidosis.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Pathobiochemistry Study Section (PBC)
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University of Washington
Schools of Medicine
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