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

色素性视网膜炎是一种遗传性视网膜变性的复合物，是日本成人致盲的第三大常见原因，发病率为1 / 5000，因此是一种重要的防盲措施。本研究旨在阐明色素性视网膜炎及其相关疾病发病的部分分子机制，为建立色素性视网膜炎及其相关疾病的治疗提供一些线索。今年作为研究的最后一个学期，我们首先继续进行了这些疾病患者分子诊断的研究项目，重点研究了一些候选基因，如peripherin/RDS、GCAP2、RDH5基因。因此，我们发现外周蛋白/RDS基因的一个新突变导致常染色体显性中央乳晕脉络膜营养不良，以及在2个常染色体显性视网膜色素变性家族中发现的GCAP2基因的新错义突变。此外，我们成功地观察到与RDH5基因突变相关的白斑眼底患者的长期眼底变化。综上所述，我们在基因型和表型之间的关系方面有了新的发现。作为研究的第二部分，我们从组织病理学、电生理和分子生物学角度研究了钙拮抗剂尼伐地平对RCS （Royal College of Surgeons大鼠）视网膜变性的影响。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小鼠改为RCS大鼠。因此，一项利用DNA尖端对基因表达进行的分析研究表明，尼维地平的使用改变了视网膜中许多基因的表达，使细胞凋亡受到抑制。我们相信这一结果为视网膜色素变性的治疗提供了新的可能性。

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.