CELLULAR METABOLISM OF AMYLOID PROTEINS IN AGING

衰老过程中淀粉样蛋白的细胞代谢

• 批准号: 2855817
• 负责人: BARBARA M SCHREIBER
• 金额: $ 23.41万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-05-01 至 2001-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2855817
• 关键词: aging; amyloid proteins; amyloidosis; apolipoproteins; cellular pathology; cholesterol; hamsters; high density lipoproteins; inflammation; lipid transport; lysosomes; macrophage; protein isoforms; protein metabolism; proteolysis; radiotracer; recombinant proteins; tissue /cell culture

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 the other involves secreted enzymes, either extracellularly or in phagolysosomes. When normal clearance is impaired, insoluble AA fibrils accumulate extracellularly. The model of spontaneous AA amyloidosis in aging female golden Syrian hamsters is ideally suited for analysis of amyloidogenic factors in the absence of confounding factors due to the massive inflammatory stimulation required by other animal models of AA amyloidogenesis; and, in particular, for assessing the pathogenetic role of SAP, a ubiquitous constituent of all amyloid deposits. We have shown that one of at least 8 closely related species of Syrian hamster apoSAA, apoSAA3, is selectively deposited spontaneously as AA fibrils. Here we propose to study apoSAA catabolism as it relates to AA amyloidosis, using recombinant apoSAA3 and nonamyloidogenic isoforms such as apoSAA1 as controls. These apoSAA molecules will be radiolabeled and used for in vivo and in vitro studies of apoSAA catabolism in hepatocytes and macrophages from young and old, amyloidotic and nonamyloidotic, 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 will be tested. We propose that apoSAA is normally cleared by dual mechanisms: type I in which apoSAA is catabolized by enzymes(s) secreted by cells of the monocyte/macrophage lineage (monocytic cell lines and peritoneal exudate cells), and type II in which apoSAA is catabolized by cell-associated enzymes(s) during cholesterol transport (e.g. hepatoma cell lines). The ability of lipids and lipoproteins, serum amyloid P (SAP) and extracellular matrix (ECM) constituents to alter the capacity of lysosomal enzymes for complete catabolism of apoSAA will be 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.

淀粉样蛋白A（AA）淀粉样变性，炎症性疾病的并发症， 如肺结核、麻风病和类风湿性关节炎， 随着未受控制的疾病的持续时间的增加。AA原纤维来源于 apoSAA蛋白（高密度的瞬时损伤特异性成分， 脂蛋白（HDL））。在急性炎症发作消退时， 升高的apoSAA似乎通过两种途径分解代谢;一种是细胞- 另一种涉及分泌酶， 或在吞噬溶酶体中。当正常清除受损时，不溶性AA 纤维在细胞外聚集。自发性AA模型 老年雌性叙利亚金黄仓鼠的淀粉样变性非常适合于 在不存在混杂因素的情况下分析淀粉样蛋白生成因子 由于其他动物需要大量的炎症刺激， AA淀粉样蛋白生成的模型;并且，特别地，用于评估 SAP的致病作用，所有淀粉样蛋白的普遍存在的成分 存款我们已经证明，至少8个密切相关的物种之一， 叙利亚仓鼠apoSAA，apoSAA 3，选择性地自发沉积， AA纤维。 在这里，我们建议研究apoSAA catalysts，因为它涉及到 使用重组apoSAA 3和非淀粉样蛋白生成亚型的AA淀粉样变性 如apoSAA 1作为对照。这些apoSAA分子将被放射性标记 并用于apoSAA催化蛋白的体内和体外研究 年轻人和老年人的肝细胞和巨噬细胞，淀粉样变性和 非淀粉样变性的雄性和雌性仓鼠。目标是获得AA原纤维 在体外系统中形成，从而建立必要的 AA原纤维形成的因素。假设apoSAA清除率 作为其正常功能的一部分， 运输将进行测试。 我们建议apoSAA通常通过以下方式清除： 双重机制：I型，其中apoSAA被酶分解代谢 由单核细胞/巨噬细胞谱系的细胞（单核细胞系）分泌 和腹膜渗出细胞），和II型，其中apoSAA被分解代谢 胆固醇转运过程中的细胞相关酶（如肝癌） 细胞系）。血脂、脂蛋白、血清淀粉样蛋白（SAP） 和细胞外基质（ECM）成分，以改变 将研究用于完全催化apoSAA的溶酶体酶。 长期目标是增强apoSAA的正常保护作用， 在恢复体内平衡，以防止功能障碍，如淀粉样变性 作为慢性炎症的并发症， 随着年龄的增长而更加普遍，并了解年龄- 调节蛋白水解的相关变化可导致淀粉样纤维 阵

项目成果

The fibril forming region of the beta-amyloid precursor differs from that of the amyloid A precursor in its interaction with lipids.

β-淀粉样蛋白前体的原纤维形成区域与淀粉样蛋白A前体的原纤维形成区域的不同之处在于其与脂质的相互作用。

• DOI: 10.1006/bbrc.1996.0332
• 发表时间: 1996
• 期刊: Biochemical and biophysical research communications
• 影响因子: 3.1
• 作者: Liang,JS;Fine,RE;Abraham,CR;Sipe,JD
• 通讯作者: Sipe,JD

Characterization of the inbred CE/J mouse strain as amyloid resistant.

• 发表时间: 1993-11
• 期刊: The American journal of pathology
• 作者: J. D. Sipe;Isabel Carreras;W. Gonnerman;Edgar S. Cathcart;Maria C. de;Beer;Frederick C. de

beta-Migrating very low density lipoprotein (beta VLDL) activates smooth muscle cell mitogen-activated protein (MAP) kinase via G protein-coupled receptor-mediated transactivation of the epidermal growth factor (EGF) receptor: effect of MAP kinase activat

β-迁移极低密度脂蛋白 (β VLDL) 通过 G 蛋白偶联受体介导的表皮生长因子 (EGF) 受体反式激活来激活平滑肌细胞丝裂原激活蛋白 (MAP) 激酶：MAP 激酶激活的作用

• DOI: 10.1074/jbc.m103761200
• 发表时间: 2001
• 期刊: The Journal of biological chemistry
• 作者: Zhao,D;Letterman,J;Schreiber,BM
• 通讯作者: Schreiber,BM

Polyarthritis and periostitis induced by Escherichia coli. Lipopolysaccharide injection in young male hamsters.

大肠杆菌引起的多关节炎和骨膜炎。

• 发表时间: 1998
• 期刊: The Journal of rheumatology.
• 作者: Gruys,E;Tooten,PC;Cathcart,ES
• 通讯作者: Cathcart,ES

Synergism of interleukin 1 and interleukin 6 induces serum amyloid A production while depressing fibrinogen: a quantitative analysis.

白细胞介素 1 和白细胞介素 6 的协同作用诱导血清淀粉样蛋白 A 的产生，同时抑制纤维蛋白原：定量分析。

• 发表时间: 1994
• 期刊: The Journal of rheumatology
• 作者: Rokita,H;Loose,LD;Bartle,LM;Sipe,JD
• 通讯作者: Sipe,JD