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综合体，被指定为日本成年人第三大常见致盲原因，发病率为每 5,000 人中就有 1 人，因此是防盲措施中的重要疾病。本研究旨在阐明色素性视网膜炎及其相关疾病发病机制的部分分子机制，并为建立这些疾病的治疗方法提供一些线索。今年，作为研究的最后一个学期，我们首先继续进行这些疾病患者的分子诊断研究项目，重点关注一些候选基因，如外周蛋白/RDS、GCAP2和RDH5基因。结果，我们发现了导致常染色体显性中央乳晕脉络膜营养不良的外周蛋白/RDS基因的新突变，以及在2个常染色体显性色素性视网膜炎家系中发现的GCAP2基因的新错义突变。此外，我们成功观察到一名白点眼底患者的长期眼底变化与 RDH5 基因的新突变有关。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，我们从组织病理学、电生理学和分子生物学角度研究了Ca2+拮抗剂尼伐地平对RCS（皇家外科学院大鼠）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，但很难获得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尖端进行的基因表达谱研究表明，尼维地平的施用改变了视网膜中许多基因的表达，从而使细胞凋亡受到抑制。我们相信这一结果为色素性视网膜炎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.