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，一种炎症并发症 结核病、麻风病和类风湿性关节炎等疾病， 随着不受控制的疾病时间的增加，这种情况发生的频率也会更高。 AA 原纤维源自 apoSAA 蛋白（瞬时、 高密度脂蛋白（HDL）的损伤特异性成分）。 在 急性炎症发作消退，apoSAA 升高 似乎通过两种途径分解代谢；一种是与细胞相关的并且 另一种涉及细胞外或细胞内的分泌酶 吞噬溶酶体。 当正常清除受损时，不溶性 AA 原纤维在细胞外积聚。 在这里我们研究apoSAA分解代谢 因为它与 AA 淀粉样变性有关，使用重组 apoSAA3 和 非淀粉样蛋白同工型，例如 apoSAA1 作为对照。 这些apoSAA 分子用于 apoSAA 的体内和体外研究 年轻和年老的肝细胞和巨噬细胞的分解代谢， 淀粉样变性和非淀粉样变性，雄性和雌性仓鼠。 目标是 在体外系统中实现 AA 原纤维形成，从而 确定 AA 原纤维形成的必要因素。 这 假设 apoSAA 清除是其正常功能的一部分 正在测试中断胆固醇反向转运的方法。 这 脂质和脂蛋白、血清淀粉样蛋白 P (SAP) 的能力 和细胞外基质（ECM）成分来改变能力 用于apoSAA完全分解代谢的溶酶体酶正在研究中 调查了。 长期目标是提高正常水平 apoSAA 在恢复体内平衡中的保护作用，以防止 功能障碍，例如淀粉样变性，是淀粉样变性的并发症 随着衰老而更加普遍的慢性炎症， 并总体了解与年龄相关的监管变化如何 蛋白水解可导致淀粉样原纤维形成。 电喷雾 电离和紫外、红外矩阵辅助激光 解吸/电离已用于验证分子量 并评估重组人 apoSAA（MW 11,832 Da）的纯度 模型肽的合成类似物，MW 2000-5000，其序列 代表 SAA 序列的关键部分。