A study on pathogenesis and therapy of the lysosomal storage disease using ON-OFF (inducible transgeneic expression) system

利用ON-OFF（诱导转基因表达）系统研究溶酶体贮积症的发病机制和治疗

基本信息

批准号：
14570757
负责人：
YAMANAKA Shoji
金额：
$ 2.18万
依托单位：
Yokohama City University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570757/
关键词：
Sandhoff disease lysosomal storage disease autoimmune disease hexosaminidase 免疫異常

项目摘要

We attemted to find the pathogenesis and therapy of the lysosomal storage disease using Sandhoff disease mice model, a model of progressive neurologic disease, via inducible transgenic gene expression system. Because of the viral and bacterial infections occured in our animal research facility, we could not build the system well.Instead, we happen to find the autoimmune features, that is very important, in the pathogenesis and development of the Sandhoff diease.Sandhoff mice rapidly develop a progressive neurologic disease of ganglioside GM2 and GA2 storage. The present study reveals that the disease-states in this model are associated with the appearance of anti-ganglioside autoantibodies. Both elevation of serum anti-ganglioside autoantibodies and IgG deposition to CNS neurons were found in the advanced stages of the Sandhoff disease in mice and serum transfer from these mice showed IgG binding to neurons. To determine the role of these autoantibodies, the Fc receptor gamma gene (FcRgamma) was additionally disrupted in Sandhoff mice, as it plays a key role in immune complex mediated autoimmune diseases. Clinical symptoms were improved and lifespans were extended in the FcRgamma deleted. Sandhoff mice and the number of apoptotic cells were also decreased. The level of ganglioside accumulation, however, did not change. IgG deposition was also confirmed in the brain of an autopsied SD patient. Taken together, these findings suggest that the production of autoantibodies plays an important role in the pathogenesis of neuropathy in Sandhoff disease and therefore provides a target for novel therapies.

我们通过使用诱导的转基因基因表达系统Sandhoff疾病小鼠模型Sandhoff疾病小鼠模型来找到溶酶体储存疾病的发病机理和治疗。由于我们的动物研究设施中发生了病毒和细菌感染，因此我们无法很好地构建该系统。立场，我们碰巧找到了自身免疫性特征，这在Sandhoff Diease的发病机理和发育中非常重要。Sandhoff小鼠迅速发展神经节苷脂GM2和GA2存储的进行性神经系统疾病。本研究表明，该模型中的疾病状态与抗绞痛自身抗体的出现有关。在小鼠Sandhoff疾病的晚期阶段发现了血清抗蛋白剂自身抗体的升高和对CNS神经元的IgG沉积，这些小鼠的血清转移都表明IgG与神经元结合。为了确定这些自身抗体的作用，FC受体伽马基因（FCRGAMMA）在Sandhoff小鼠中又受到了破坏，因为它在免疫复杂介导的自身免疫性疾病中起关键作用。改善了临床症状，并在FCRGAMMA中延长了寿命。 Sandhoff小鼠和凋亡细胞的数量也减少了。但是，神经节苷脂的积累水平没有改变。在尸检SD患者的大脑中也证实了IgG沉积。综上所述，这些发现表明，自身抗体的产生在Sandhoff疾病中神经病的发病机理中起重要作用，因此为新疗法提供了靶标。