Systemic reactive amyloidosis is a rare but frequently fatal complication of chronic inflammatory diseases. The disorder appears to arise when a normal blood protein, serum amyloid A (SAA), is incompletely catabolized and deposited as amyloid A (AA) in tissues. SAA, which is transported with the plasma high density lipoproteins (HDL), has been characterized. We propose to investigate the transport of SAA in human plasma, to study the metabolism of SAA in subhuman species, and to directly test the hypothesis that SAA is the precursor of AA. We will define the spectrum of SAA-containing particles in the plasma of volunteers suffering an experimental acute-phase response and in the plasma of patients with acute and chronic inflammatory diseases and familial HDL deficiency (Tangier disease). Subhuman primates will be used to determine the magnitude and source of SAA transported in monkey lymph and the fate of SAA bound to chylomicrons and HDL. SAA tissue clearance and/or deposition will be studied in normal mice and in animals in the pre-amyloid and deposition phases of amyloidosis. In many studies we will use recently introduced radioactive tracers that remain intracellular after tissue uptake. Tissue sites of normal SAA clearance will be identified, and studies will be undertaken using the isolated, perfused rabbit liver and liver cells in monolayer culture to define the normal mechanisms of SAA catabolism. The dependence of SAA clearance on extracellular proteolysis will be examined and we will attempt to identify the clotting factor which activates an SAA protease in serum. Finally, we will seek direct evidence that SAA is converted to AA.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL026156-05
Application #
3338489
Study Section
Biochemistry Study Section (BIO)
Project Start
1981-05-01
Project End
1988-01-31
Budget Start
1986-02-01
Budget End
1987-01-31
Support Year
5
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Miriam Hospital
Department
Type
DUNS #
039318308
City
Providence
State
RI
Country
United States
Zip Code
02906
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Bausserman, L L; Saritelli, A L; Van Zuiden, P et al. (1987) Degradation of serum amyloid A by isolated perfused rat liver. J Biol Chem 262:1583-9
Herbert, P N; Bausserman, L L; Lynch, K M et al. (1987) Homologues of the human C and A apolipoproteins in the Macaca fascicularis (cynomolgus) monkey. Biochemistry 26:1457-63