Oxygen toxicity as a factor in retinal degenerations: genetic and environmental mechanisms

该项目将探索一组称为视网膜色素变性(RP)的致盲疾病背后的机制。它们是由眼睛视网膜的感光细胞(光感受器)死亡或死亡引起的。众所周知，许多形式的RP是由基因突变引起的，但许多病例(40%-50%)是零星发生的，即没有家族病史。此外，越来越多的证据表明，这种疾病的遗传形式的进展速度受到环境因素的强烈影响，特别是光和氧气。为了分析这些环境因素如何影响视网膜的稳定性，我们将使用一系列技术(包括基因阵列技术)来研究将光或氧气应激与光感受器死亡联系起来的分子事件。这项工作将在这种疾病的小鼠模型上进行。啮齿类动物(大鼠和小鼠)的视网膜和人类的视网膜具有共同的基本结构和功能细节，这一点越来越得到证实。这些模型允许进行深入的调查，其结果直接适用于人类疾病。我们的重点将主要放在这些模型的三个方面：(1)光应激或氧气应激在视网膜中诱导的分子机制；(2)线粒体(对细胞新陈代谢和细胞稳定至关重要的细胞器)的作用；以及(3)调节光感受器对氧气胁迫的脆弱性的基因。近100年来，人们一直认为RP是导致年轻人失明的主要原因。它通常在年轻人中被诊断为夜视障碍，但预后严峻(无情地进行性视力丧失)，仍然没有有效的治疗方法。建议的工作将有助于我们理解所涉及的基本机制，并将探索一些治疗或至少减轻RP失明的方法。

This project will explore the mechanisms underlying a group of blinding diseases called Retinitis Pigmentosa (RP). They are caused by the death or degneration of the light-receptive cells of the retina of the eye (photoreceptors). It is well established that many forms of RP are caused by genetic mutations but many cases (40-50%) occur 'sporadically', i.e. without a family history. Further there is growing evidence that the rate at which genetic forms of the disease progress is strongly influenced by environmental factors, particularly light and oxygen. To analyse how these environmental factors affect the stability of the retina, we will use a range of techniques (including gene array technology) to study the molecular events which link light or oxygen stress to photoreceptor death. The work will be done in mouse 'models' of the disease. It is increasingly well established that the rodent (rat and mouse) retina and human retina share a basic structure and functional detail. These models allow intensive investigation, with results which are directly applicable to human disease. Our principal emphasis will be on three aspects of these models: (1) the molecular mechanisms induced in the retina by light stress or oxygen stress; (2) the role of mitochondria (cellular organelles essential for both cell metabolism and cell stability; and (3) genes which regulate the vulnerability of photoreceptors to oxygen stress. RP has been recognised for nearly 100 years as a leading cause of blindness in young adults. It is usually diagnosed in the young adult as a failure of night vision, but the prognosis is grim (relentlessly progressive loss of vision), and there is still no effective treatment. The work proposed will contribute to our understanding of the basic mechanisms involved, and will explore some approaches to therapy for, or at least to mitigation of the blindness of RP.