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.

色素性视网膜炎是遗传性视网膜变性的复杂性，被提名为日本成年人口中第三个最常见的失明原因，其中5,000人中有1人，因此在反对失明的措施方面是一种重要疾病。本研究旨在阐明色素性视网膜炎及其相关疾病的发病机理的一部分，并获得一些用于建立这些疾病治疗的线索。今年，作为研究的最后一项，我们首先继续研究这些疾病患者的分子诊断项目，这些疾病重点是某些候选基因，例如外围蛋白/RDS，GCAP2和RDH5基因。作为一种疾病，我们已经确定了外周/RDS基因的新型突变，从而导致常染色体占主型乳鼻脉络膜营养不良，并在2个常染色体显性视网膜炎的家族中发现的GCAP2基因中的新型错义突变。此外，我们成功地观察到了与RDH5基因中新型突变相关的眼底心脏病患者的长期眼底变化。总而言之，我们在基因型和表型之间的关系中获得了新的发现。作为研究的第二部分，我们研究了CA拮抗剂Nilvadipine对RCS（皇家外科医生大鼠）视网膜变性的影响，从组织病理学，电学学和分子在生物学上。尽管我们首先设计将RDS Mouce用于治疗研究，但很难获得RDS小鼠，因此我们将研究重点从RDS小鼠转变为RCS大鼠。结果，使用DNA尖端对基因表达的PRO归档研究表明，尼尔维地汀的给药改变了视网膜中许多基因的表达，从而抑制了细胞凋亡的状况。我们认为，这一结果为治疗视网膜炎色素的治疗提供了新的可能性。