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

氧中毒是视网膜变性的一个因素：遗传和环境机制

• 批准号: nhmrc : 268060
• 负责人: Prof Jonathan Stone
• 金额: $ 17.95万
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2004
• 资助国家: 澳大利亚
• 起止时间: 2004-01-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/oxygen-toxicity-factor-environmental-mechanisms/97200
• 关键词: Oxygen; toxicity; factor; retinal; degenerations

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.

这个项目将探讨一组致盲疾病的机制，称为视网膜色素变性（RP）。它们是由眼睛视网膜的光感受细胞（光感受器）的死亡或退化引起的。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%）“零星”发生，即没有家族史。此外，越来越多的证据表明，遗传形式的疾病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）来研究将光或氧应激与感光细胞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”中进行。啮齿类动物（大鼠和小鼠）视网膜和人类视网膜共享基本结构和功能细节，这一点越来越得到证实。这些模型允许深入研究，其结果直接适用于人类疾病。我们的主要重点将放在这些模型的三个方面：（1）光应激或氧应激在视网膜中诱导的分子机制;（2）线粒体（细胞代谢和细胞稳定所必需的细胞器）的作用;（3）调节光感受器对氧应激的脆弱性的基因。近100年来，RP一直被认为是年轻人失明的主要原因。它通常在年轻人中被诊断为夜间视力的失败，但预后是严峻的（无情地进行性视力丧失），并且仍然没有有效的治疗方法。这项工作将有助于我们了解所涉及的基本机制，并将探索一些方法来治疗，或至少减轻失明的RP。