DEVELOPMENT OF MODEL MOUSE FOR DIALYSIS-RELATED AMYLOIDOSIS AND ITS APPLICATION FOR THE ANALYSIS OF PATHOGENESIS.

长期透析常伴淀粉样蛋白沉积，主要见于关节滑膜。淀粉样蛋白沉积是严重的透析并发症，严重恶化长期透析患者的生活质量。淀粉样蛋白沉积的主要成分是β 2-微球蛋白（β 2-m），其分子量为11,800道尔顿。这种淀粉样蛋白的淀粉样蛋白形成的细节尚不清楚。目前，已经提出了多种导致其发病的因素。它们包括钙、淀粉样蛋白P组分、糖胺聚糖和胶原蛋白。此外，巨噬细胞、单因子、蛋白酶、自由基和载脂蛋白E也被认为在淀粉样蛋白纤维的形成中起作用。虽然这一机制可能是多因素的，但β 2-m的保留被认为是触发这一过程的主要条件，β 2-m是这种淀粉样蛋白的前体蛋白。为了分析透析相关淀粉样变中淀粉样蛋白沉积的机制，我们试图建立一种淀粉样变模型小鼠。通过微注射连接MML病毒DNA的人β 2-m cDNA作为启动子，建立了转基因小鼠。取3 ~ 6月龄小鼠的滑膜和其他器官，进行组织病理学和免疫组织化学检查。除肝脏外，其他脏器未见刚果红阳性病变，β 2-m抗体未见明显染色。长期随访观察的研究仍在进行中。

Long-term dialysis is very often complicated with amyloid deposits, predominantly in aricular synovial membranes. The amyloid deposition is a serious complication of dialysis as it excessively deteriorates the quality of life of long-term dialysis patients. A major component of amyloid deposits was identified as beta2-microglobulin (beta2-m) having a molecular weight of 11,800 daltons.The details of amyloidogenesis of this type of amyloid remain unknown. At present, a variety of the factors contributing to the pathogenesis have been proposed. They include calcium, amyloid P component, glycosaminoglycans, and collagens. Furthermore, macrophages, monokines, proteases, free radicals, and apolipoprotein E are also suggested to play roles in amyloid fibril formation. Although the mechanism is probably multifactorial, the retention of beta2-m, that is a precursor protein of this type of amyloid, is considered to be a principal requirement for the trigger of this processes.To analyze the mechanisms of amyloid deposition in dialysis-related amyloidosis, we have tried to develop a model mouse for the amyloidosis. Transgenic mice by microinjecting human beta2-m cDNA ligated with a MML virus DNA as a promoter were developed.Synovia and other organs were obtained from mice sacrificed at the age of between 3 months and 6 months, and examined histopathologically and immunohistochemically.There was no Congo red positive lesion in any organs and no significant staining with beta2-m antibody except liver.Studies are still in progress with long-term follow-up observation.