MEDIATION OF ANTIBODY INDUCED GLOMERULAR INJURY

抗体引起的肾小球损伤的调节

• 批准号: 6345251
• 负责人: DAVID J SALANT
• 金额: $ 0.31万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6345251
• 关键词: aging; animal tissue; biological products; biomedical resource; biotechnology; immunology; inflammation; nervous system; structural biology

Amyloid A (AA) amyloidosis, a complication of inflammatory diseases such as tuberculosis, leprosy and rheumatoid arthritis, occurs more frequently with increasing length of unchecked disease. AA fibrils are derived from apoSAA proteins (transient, injury-specific constituents of high density lipoprotein (HDL)). At the resolution of an acute inflammatory episode, elevated apoSAA appears to be catabolized by two pathways; one is cell-associated and theother involves secreted enzymes, either extracellularly or in phagolysosomes. When normal clearance is impaired, insoluble AA fibrils accumulate extracellularly. Here we study apoSAA catabolism as it relates to AA amyloidosis, using recombinant apoSAA3 and nonamyloidogenic isoforms such as apoSAA1 as controls. These apoSAA molecules are used for in vivo and in vitro studies of apoSAA catabolism in hepatocytes and macrophages from young and old, amyloidotic andnonamyloidotic, male and female hamsters. The goal is to achieve AA fibril formation in a deemed in vitro system, thereby establishing the requisite factors for AA fibril formation. The hypothesis that apoSAA clearance occurs as part of its normal function to interrupt reverse cholesterol transport is being tested. The ability of lipids and lipoproteins, serum amyloid P (SAP) andextracellular matrix (ECM) constituents to alter the capacity of lysosomal enzymes for complete catabolism of apoSAA is being investigated. The long range goals are to enhance the normal protective role of apoSAA in restoration of homeostasis, to prevent dysfunctions such as amyloidosis that occur as a complication of the chronic inflammatory conditions that are more prevalent with aging, and to understand in general how age-associated changes in regulated proteolysis can lead to amyloid fibril formation. Electrospray ionization and ultraviolet and infrared matrix-assisted laser desorption/ionization have been used to verify the molecular weights andevaluate purity of recombinant human apoSAA, MW 11,832 Da, and of synthetic analogs of model peptides, MWs 2000-5000, whose sequences represent key portions of the SAA sequence.

淀粉样蛋白A （AA）淀粉样变性，炎症的并发症