MEDIATION OF ANTIBODY INDUCED GLOMERULAR INJURY

抗体引起的肾小球损伤的调节

• 批准号: 6478975
• 负责人: DAVID J SALANT
• 金额: $ 5.36万
• 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/6478975
• 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.

炎症性并发症--淀粉样蛋白A(AA) 结核病、麻风病和类风湿性关节炎等疾病， 随着未经控制的疾病的持续时间的增加，发生的频率也越来越高。 AA原纤维来源于apoSAA蛋白(瞬时， 高密度脂蛋白(高密度脂蛋白)的损伤特异性成分)。在… 急性炎症发作的解决，apoSAA升高 似乎被两条途径分解；一条是细胞相关的和 另一种是细胞外或细胞内的分泌酶。 吞噬酶体。当正常间隙受损时，不溶AA 纤维在细胞外堆积。在这里我们研究载脂蛋白A的分解代谢 因为它与AA淀粉样变性有关，所以使用重组apoSAA3和 非淀粉样变异构体，如apoSAA1作为对照。这些aposaa 载脂蛋白SAA分子用于体内和体外研究 青年和老年人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。我们的目标是 在被认为是体外系统中实现AA原纤维的形成，从而 确定了AA原纤维形成的必要条件。这个 假设apoSAA清除是其正常功能的一部分 阻断胆固醇反向运输的方法正在测试中。这个 血脂和脂蛋白能力、血清淀粉样蛋白P(SAP) 和细胞外基质(ECM)成分改变细胞的能力 完全分解apoSAA的溶酶体酶正在研究中 调查过了。长期的目标是提高正常的 载脂蛋白A在体内平衡恢复中的保护作用 功能障碍，如淀粉样变性，发生于 随着年龄的增长，慢性炎症性疾病更加普遍， 并大体上了解年龄相关的变化是如何调控的 蛋白分解可导致淀粉样原纤维的形成。电喷雾 电离与紫外和红外基质辅助激光器 用解吸/电离的方法验证了分子量 重组人apoSAA分子量为11,832 Da， 模型多肽的合成类似物，MWS 2000-5000，其序列 代表SAA序列的关键部分。