Although retinitis pigmentosa (RP) is most frequently studied in mouse models, rats, rabbits, and pigs are also used as animal models of RP. However, no studies have reported postnatal photoreceptor cell loss before complete development in these models. Here, we generated a transgenic rat strain, named the P347L rat, in which proline at position 347 in the rhodopsin protein was replaced with leucine. A pathological analysis of photoreceptor cells in the P347L rat model was performed, and drugs with potential use as therapeutic agents against RP were investigated. The data clearly showed rapid degeneration and elimination of the outer nuclear layer even before the photoreceptor cells were fully established in P347L rats. To test the usefulness of the P347L rat in the search for new therapeutic agents against RP, the effects of rapamycin on RP were investigated in this rat strain. The findings suggest that rapamycin promotes autophagy and autophagosomal uptake of the rhodopsin that has accumulated abnormally in the cytoplasm, thereby alleviating stress and delaying photoreceptor cell death. In this RP model, the time to onset of retinal degeneration was less than that of previously reported RP models with other rhodopsin mutations, enabling quicker in vivo evaluation of drug efficacy. Administration of rapamycin delayed the photoreceptor cell degeneration by approximately 1 day.

中文翻译：

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具有快速视网膜变性的视网膜色素变性大鼠模型能够进行体内药物评估

虽然视网膜色素变性 (RP) 最常在小鼠模型中进行研究，但大鼠、兔和猪也被用作 RP 的动物模型。然而，没有研究报告在这些模型中完全发育之前出生后光感受器细胞的损失。在这里，我们生成了一个转基因大鼠品系，命名为 P347L 大鼠，其中视紫质蛋白 347 位的脯氨酸被亮氨酸取代。对 P347L 大鼠模型中的光感受器细胞进行了病理分析，并研究了可能用作抗 RP 治疗剂的药物。数据清楚地表明，甚至在 P347L 大鼠的感光细胞完全建立之前，外核层就迅速退化和消除。为了测试 P347L 大鼠在寻找针对 RP 的新治疗剂方面的有用性，在该大鼠品系中研究了雷帕霉素对 RP 的影响。研究结果表明，雷帕霉素促进细胞质中异常积累的视紫红质的自噬和自噬体​​摄取，从而减轻压力并延迟光感受器细胞死亡。在这个 RP 模型中，视网膜变性发生的时间比之前报道的具有其他视紫红质突变的 RP 模型要短，从而能够更快地在体内评估药物功效。雷帕霉素的给药将光感受器细胞变性延迟了大约 1 天。视网膜变性发生的时间比之前报道的具有其他视紫红质突变的 RP 模型要短，从而能够更快地在体内评估药物功效。雷帕霉素的给药将光感受器细胞变性延迟了大约 1 天。视网膜变性发生的时间比之前报道的具有其他视紫红质突变的 RP 模型要短，从而能够更快地在体内评估药物功效。雷帕霉素的给药将光感受器细胞变性延迟了大约 1 天。