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: 3120817
• 负责人: Jean D Sipe
• 金额: $ 17.34万
• 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 1994-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3120817
• 关键词: aging; amyloid proteins; amyloidosis; conformation; disease /disorder model; eicosanoids; gene expression; genetic strain; hamsters; high density lipoproteins; macrophage; myofibrils; nutrition related tag; phagocytosis; proteolysis

The overall objective is to define the natural history of spontaneous amyloidosis in hamsters and the cellular impairments of protein degradation that are common to age-associated amyloidoses. The aging golden Syrian hamster exhibits a striking gender difference in life span and in susceptibility to amyloid A (AA) fibril formation and deposition, with 100% incidence in female hamsters by 1.5 years, but only 25% in male hamsters at 3 years. In addition, female, but not male, hamsters have high concentrations of the amyloid P (AP) component analogue female protein (FP). Amyloidosis is the endpoint of a sequence of events in which SAA is transported by high density lipoprotein (HDL) through the bloodstream to peripheral tissues and incompletely degraded by mononuclear phagocytes, resulting in an exponential accumulation of AA fibrils in extracellular spaces. It is not known whether extracellular dissociation of apoSAA from HDL plays a critical role in amyloidosis, or whether SAA gene expression and AP secretion influence macrophage capacity for SAA proteolysis. It is postulated that there is a causal relationship between the pentraxin FP and impaired degradation of the AA fibril precursor serum amyloid A (SAA). Specifically, we will determine: 1) Whether the development of AA amyloidosis with aging is correlated with plasma FP concentrations a) in male and female amyloidosis-susceptible Syrian hamsters and amyloidosis- resistant Armenian hamsters b) in young and old hamsters in which amyloidosis is experimentally induced by dietary or subcutaneously injected casein; 2) Whether the degradation of SAA a) is restricted to cells of the mononuclear phagocyte series or occurs in cells of other lineages b) occurs intracellularly following uptake of SAA/HDL or apoSAA or c) is a function of the physicochemical form of SAA (SAA/HDL complex v. apoSAA) or the isotype structure of apoSAA; 3) Whether the capacity of mononuclear phagocytes to completely digest SAA is a) related to hamster strain, age and the concentration of FP in plasma b) affected by the FP or SAA gene expression c) directly or indirectly altered by FP. These studies will provide fundamental knowledge for logical therapeutic intervention in human amyloidosis and for enhancement of host defense with aging.

总的目标是界定自然历史的自发 仓鼠的淀粉样变性和蛋白质降解的细胞损伤 与年龄相关的淀粉样变性很常见 上了年纪的金色叙利亚人 仓鼠在寿命和 对淀粉样蛋白A（AA）纤维形成和沉积的敏感性，100% 在雌性仓鼠中，1.5年后的发病率为25%，但在雄性仓鼠中， 3年 此外，雌性而非雄性仓鼠具有高的 淀粉样蛋白P（AP）组分类似物雌性蛋白的浓度 （FP）。 淀粉样变性是一系列事件的终点，其中SAA是 由高密度脂蛋白（HDL）通过血液运输， 外周组织和单核吞噬细胞不完全降解， 导致细胞外AA原纤维呈指数级积累 空间. 目前尚不清楚apoSAA在细胞外的解离是否与细胞凋亡有关。 HDL在淀粉样变中起着关键作用，或者SAA基因表达 和AP分泌影响巨噬细胞SAA蛋白水解的能力。 是 假设五聚体FP和 AA原纤维前体血清淀粉样蛋白A（SAA）的降解受损。 具体而言，我们将确定：1）是否发展AA 淀粉样变性伴衰老与血浆FP浓度相关 雄性和雌性淀粉样变性易感的叙利亚仓鼠和淀粉样变性- 抗性亚美尼亚仓鼠B）在年轻和年老仓鼠中，其中 淀粉样变性是通过饮食或皮下注射 a）SAA的降解是否限于酪蛋白的细胞; 2）SAA的降解是否限于酪蛋白的细胞; 单核吞噬细胞系列或出现在其他谱系的细胞中B） 在SAA/HDL或apoSAA摄取后在细胞内发生，或c）是 SAA的物理化学形式的功能（SAA/HDL复合物v. apoSAA）或 apoSAA的同种型结构; 3）单核细胞的能力是否 吞噬细胞完全消化SAA的能力与仓鼠品系、年龄有关 以及受FP或SAA基因影响的血浆中FP的浓度，B） 表达c）被FP直接或间接改变。 这些研究将 为人类的合理治疗干预提供基础知识 淀粉样变性和增强宿主对衰老的防御。