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A Study of Molecular Pathogenesis and Treatment of Retinitis Pigmentosa and Allied Diseases

色素性视网膜炎及相关疾病的分子发病机制及治疗研究

基本信息

批准号：
11470361
负责人：
NAKAZAWA Mitsuru
金额：
$ 9.47万
依托单位：
Hirosaki University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11470361/
关键词：
retinitis pigmentosa fundus albipuntatus peripherin RDS gene RDH5 gene RCS rat nilvadipine ペリフェリン RDS遺伝子 RDS RP1遺伝子

项目摘要

Retinitis pigmentosa is a complex of hereditary retinal degenerations that is nominated as the third commonest cause of blindness in adult population in Japan with the incidence of 1 out of 5,000 people, and therefore is an important disease in terms of measures against blindness. The present study was designed to clarify parts of molecular mechanisms of pathogenesis of retinitis pigmentosa and its allied diseases and to obtain some clues for establishment of treatment for these diseases. This year, as the last term of periods of the research, we, first of all, had continued research project of molecular diagnosis of patients with these diseases focusing on some candidate genes such as peripherin/RDS, GCAP2, and RDH5 genes. As a esult, we have identified a novel mutation of the peripherin/RDS gene causing autosomal dominant central areolar choroidal dystrophy, and novel missense mutation in the GCAP2 gene found in 2 families with autosomal dominant retinitis pigmentosa. Moreover, we successfully observed a long term fundus changes of a patient with Fundus Albipunctatus associated with a novel mutation in the RDH5 gene. In summary, we have obtained new findings in the relationship between genotypes and phenotypes. As the second part of the study, we investigated the effect of Ca antagonist, nilvadipine, on the retinal degeneration of RCS (Royal College of Surgeons rat) histopathologically, electrophisiologically, and molecular biologically. Although we first designed to use rds mouce for treatment study, it was difficult to obtain rds mice and therefore we changed research focus from rds mice to RCS rats. As a result, a pro filing study of gene expression using DNA tip indicated that administration of nilvidipine changed expressions of many genes in the retina toward the condition in which apoptosis was inhibited. We believe that this result provides new possibility for the treatment of retinitis pigmentosa.

色素性视网膜炎是一种遗传性视网膜变性的综合症，在日本被提名为成人人群中第三大最常见的致盲原因，发病率为1/5，000，因此在防盲措施方面是一种重要的疾病。本研究旨在阐明视网膜色素变性及其类缘病发病的部分分子机制，并为这些疾病的治疗提供线索。今年，作为该研究的最后一个学期，我们首先继续开展了这些疾病患者的分子诊断研究项目，重点是外周蛋白/RDS，GCAP 2和RDH 5基因等候选基因。因此，我们发现了一个新的外周蛋白/RDS基因突变导致常染色体显性遗传中心晕状脉络膜营养不良，和新的错义突变的GCAP 2基因中发现的2个常染色体显性遗传视网膜色素变性的家庭。此外，我们成功地观察到一个长期的眼底变化的患者与眼底白斑与一个新的突变在RDH 5基因。总之，我们在基因型和表型之间的关系方面获得了新的发现。作为研究的第二部分，我们研究了钙拮抗剂尼伐地平对皇家外科医学院大鼠（RCS）视网膜变性的组织病理学、电生理学和分子生物学的影响。虽然我们最初设计使用rds小鼠进行治疗研究，但由于难以获得rds小鼠，因此我们将研究重点从rds小鼠转移到RCS大鼠。结果，使用DNA tip的基因表达的分析研究表明，给予尼维地平改变了视网膜中许多基因的表达，使其趋向于细胞凋亡被抑制的状态。我们认为这一结果为视网膜色素变性的治疗提供了新的可能性。