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: 3120816
• 负责人: Jean D Sipe
• 金额: $ 16.68万
• 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/3120816
• 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.

总体目标是定义自发性的自然历史 仓鼠淀粉样变性与蛋白质降解的细胞损伤 这在年龄相关的淀粉样变性中很常见。年迈的金色叙利亚人 仓鼠在寿命和年龄上表现出显著的性别差异 对淀粉样蛋白A(AA)纤维的形成和沉积易感性，100% 雌性仓鼠的发病率增加了1.5年，但雄性仓鼠的发病率仅为25% 三年了。此外，雌性仓鼠，但不是雄性仓鼠，有很高的 淀粉样蛋白P(AP)成分类似物女性蛋白的浓度 (Fp)。淀粉样变性是SAA发生的一系列事件的终点 由高密度脂蛋白(高密度脂蛋白)通过血液输送到 周围组织，并被单核吞噬细胞不完全降解， 导致胞外AA纤维呈指数级积累 空格。目前尚不清楚apoSAA的胞外解离是否来自 高密度脂蛋白在淀粉样变性或SAA基因表达中起关键作用 AP的分泌影响巨噬细胞对SAA蛋白的降解能力。它是 假设在五星蛋白和FP之间存在因果关系 AA纤维前体血清淀粉样蛋白A(SAA)的降解受损。 具体来说，我们将确定：1)AA的发展是否 老年人淀粉样变性与血浆Fp浓度a)相关 雄性和雌性淀粉样变性-易感叙利亚仓鼠和淀粉样变性- 耐受的亚美尼亚仓鼠b)在幼龄仓鼠和老年仓鼠中 实验性淀粉样变性是由饮食或皮下注射引起的 酪蛋白；2)SAA a)的降解是否仅限于 单核吞噬细胞系列或出现在其他谱系的细胞中。 在摄取SAA/HDL或apoSAA或c)后发生在细胞内 SAA的物理化学形式的功能(SAA/高密度脂蛋白复合体诉apoSAA)或 ApoSAA的同型结构；3)单核细胞的能力 吞噬细胞完全消化SAA是a)与仓鼠品系、年龄有关 以及受FP或SAA基因影响的血浆中FP浓度 表达式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 淀粉样变性和随年龄增长的宿主防御能力增强。