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Metabolism of amyloid proteins and methods for detecting amyloid proteins

淀粉样蛋白的代谢和检测淀粉样蛋白的方法

基本信息

批准号：
21790541
负责人：
UEDA Mitsuharu
金额：
$ 2.75万
依托单位：
Kumamoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Young Scientists (B)
财政年份：
2009
资助国家：
日本
起止时间：
2009 至 2010
项目状态：
已结题

项目摘要

Systemic AA amyloidosis is one of the most severe complications of chronic inflammatory disorders, particularly rheumatoid arthritis. It is well known that, similar to an infectious prion protein, amyloid-enhancing factor (AEF) acts as a transmissible agent in AA amyloidosis. However, how AEF transmits AA amyloidosis in vivo remained to be fully elucidated. In the present study, we focused on finding cell-free forms of AEF and its carriers in circulation by using the murine transfer model of AA amyloidosis. We first determined that circulating cell-free AEF existed in blood and plasma in mice with systemic AA amyloidosis. Second, we established that plasma exosomes containing AA amyloid oligomers derived from serum amyloid A had AEF activity and could transmit systemic AA amyloidosis via a prion-like mechanism. These novel findings should provide insights into the transmission mechanism of systemic amyloidoses.We previously reported that two cases of aged vervet monkeys (Cercopithecus … More aethiops) spontaneously developed TTR amyloidosis and showed clinical symptoms mimicking human TTR amyloidosis. However, the pathogenesis of TTR amyloidosis in vervet monkeys and relationship to the human disease remained to be elucidated. The aims of the present study were to elucidate the pathogenesis of TTR amyloidosis in the vervet monkeys, and to verify pathological relationship to the human TTR amyloidosis. First, using over 120 tissue specimens of various primates and clinical cardiac findings of vervet monkeys and crab-eating macaques, we showed that aged vervet monkeys developed TTR amyloidosis mainly causing cardiac dysfunction by means of physicochemical examinations, but other non-human primates showed neither TTR amyloid deposits nor cardiac dysfunctions. Next, we determined that vervet monkeys had the species-specific TTR allele. Taken together, we propose that the aged vervet monkeys mimic the human TTR amyloidosis and the monkey is a precious species as an animal model for this hereditary disease of human. Less

系统性AA淀粉样变性是慢性炎症性疾病，特别是类风湿性关节炎的最严重并发症之一。众所周知，与感染性朊病毒蛋白类似，淀粉样蛋白增强因子（AEF）在AA淀粉样变性中作为一种传播因子。然而，AEF如何在体内传播AA淀粉样变性仍有待充分阐明。在本研究中，我们的重点是寻找无细胞形式的AEF及其载体在循环中使用小鼠转移模型的AA淀粉样变性。我们首先确定了循环无细胞AEF存在于系统性AA淀粉样变性小鼠的血液和血浆中。其次，我们确定了含有来源于血清淀粉样蛋白A的AA淀粉样蛋白寡聚体的血浆外泌体具有AEF活性，并且可以通过朊病毒样机制传播系统性AA淀粉样变性。这些新的发现将为系统性淀粉样变性的传播机制提供新的见解。我们以前报道了两例老年长尾猴（Cercopithecus ...更多信息 aethiops）自发地发生TTR淀粉样变性，并显示出类似于人TTR淀粉样变性的临床症状。然而，在长尾猴TTR淀粉样变性的发病机制和人类疾病的关系仍有待阐明。本研究的目的是阐明恒河猴TTR淀粉样变性的发病机制，并验证其与人类TTR淀粉样变性的病理关系。首先，我们使用超过120个不同灵长类动物的组织标本和临床心脏发现的长尾猴和食蟹猕猴，我们表明，老年长尾猴发展TTR淀粉样变性主要导致心脏功能障碍的理化检查手段，但其他非人类灵长类动物没有TTR淀粉样蛋白沉积或心脏功能障碍。接下来，我们确定黑长尾猴具有物种特异性TTR等位基因。综合以上结果，我们认为，老年黑长尾猴是模拟人类TTR淀粉样变性的动物模型，是研究人类TTR淀粉样变性的一种珍贵动物。少