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Study on Molecular pathology of cancer associated retinopathy

癌相关性视网膜病变的分子病理学研究

基本信息

批准号：
11671749
负责人：
OHGURO Hiroshi
金额：
$ 2.5万
依托单位：
Sapporo Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

项目摘要

A visual paraneoplastic syndrome called cancer-associated retinopathy(CAR) has been identified in patients with small cell carcinoma of lung and other malignant tumors. These patients are clinically characterized with photopsia, progressive visual loss with a ring scotoma, attenuated retinal arterioles, and abnormalities of the a- and b-waves of the ERG.Histopathological and immunological observations revealed that, in CAR, loss of photoreceptor cells may be caused by an autoimmune reaction against a photoreceptor specific 23 kDa calcium binding protein called recoverin. Functionally, recoverin was found to play a major role in light and dark adaptation by regulating rhodopsin phosphorylation and dephosphorylation in a calcium-dependent manner. Recently, expression of recoverin has been identified in the cancer cells of CAR patients, and expression of the CAR antigen(recoverin)is induced by an intraperitoneal cultivation of small-cell carcinoma. These observations allowed us to speculate that aberrant expression of recoverin in cancer cells may trigger an autoimmune reaction. In addition, other retinal antigens including 65 kDa protein, 48 kDa protein, enolase(46 kDa protein), and neurofilament(58-62 kDa, 145 kDa and 205 kDa proteins)are recognized by some CAR patients' sera. Among these retinal autoantigens, recoverin alone or a combination of recoverin and 65 kDa protein have most frequently been shown as the immunoreactive bands in western blot analysis in the previous reports. Most recently our group identified the 65 kDa protein as heat shock cognate protein 70(hsc 70). Therefore, we suggested that both anti-recoverin and anti-hsc 70 antibodies are involved in the pathogenesis of CAR.In the present study, to further investigate the pathological roles of anti-recoverin and anti-hsc 70 antibodies in CAR, we injected these antibodies into the vitreous cavity of Lewis rats, and performed histopathological and electrophysiological characterization of the retinas.

一种视觉副肿瘤综合征，称为癌症相关性视网膜病变（CAR），已在肺小细胞癌和其他恶性肿瘤患者中发现。这些患者的临床特征为视网膜变性、伴有环状暗点的进行性视力丧失、视网膜小动脉变细以及ERG的a波和b波异常。组织学和免疫学观察显示，在CAR中，感光细胞的丧失可能是由针对感光细胞特异性23 kDa钙结合蛋白（称为恢复素）的自身免疫反应引起的。在功能上，recoverin被发现在光和暗适应中发挥重要作用，通过调节视紫红质磷酸化和去磷酸化的钙依赖性的方式。最近，已经在CAR患者的癌细胞中鉴定了恢复蛋白的表达，并且CAR抗原（恢复蛋白）的表达通过小细胞癌的腹膜内培养来诱导。这些观察使我们能够推测癌细胞中恢复蛋白的异常表达可能引发自身免疫反应。此外，一些CAR患者的血清还识别其他视网膜抗原，包括65 kDa蛋白质、48 kDa蛋白质、烯醇化酶（46 kDa蛋白质）和神经丝（58-62 kDa、145 kDa和205 kDa蛋白质）。在这些视网膜自身抗原中，recoverin单独或recoverin和65 kDa蛋白的组合在以前的报道中最常显示为Western印迹分析中的免疫反应性条带。最近，我们的小组确定了65 kDa的蛋白为热休克同源蛋白70（hsc 70）。因此，我们认为抗-recoverin和抗-hsc 70抗体均参与了CAR的发病过程。为了进一步研究抗-recoverin和抗-hsc 70抗体在CAR中的病理作用，我们将这些抗体注射到刘易斯大鼠的玻璃体腔中，并进行视网膜的组织病理学和电生理学表征。