Role and Molecular Mechanisms of Corneal Aldehyde Dehydrogenase

项目摘要 这个项目的长期目标是阐明乙醛脱氢酶(ALDH3A1和ALDH3A1)的作用 ALDH1A1)在抵御紫外线辐射(UVR)毒性的眼部防御机制中的作用。众所周知， UVR诱导的活性氧物种(ROS)导致膜脂过氧化和 有毒的醛，如4-羟基-2-壬烯醛(4-HNE)。ALDH3A1和ALDH1A1都能解毒4-HNE， 与多种疾病的发病机制有关，包括白内障和视网膜变性 疾病。在过去的资助期间，我们在以下方面取得了新的重大发现： ALDH3A1和ALDH1A1对眼部氧化应激的保护作用我们发现这两种酶都能保护 抗UVR和4-HNE诱导的细胞毒性，至少ALDH3A1可能起到UVR滤膜保护作用 其他酶的失活。最后，也是最重要的，我们发现Aldh3a1(-/-)和 ALDH1A1(-/-)/Aldh3a1(-/-)基因敲除小鼠在生命早期就会出现前囊和后囊下白内障， 而Aldh1a1(-/-)基因敲除动物在晚年会患上白内障。这些新颖的数据支持我们的工作 假设角膜ALDH3A1和晶状体ALDH1A1通过非 酶(滤光)和酶(解毒)功能。

Project Summary The long term goal of this project is to elucidate the role of aldehyde dehydrogenases (ALDH3A1 and ALDH1A1) in the ocular defense mechanism against ultraviolet radiation (UVR) toxicity. It is well known that UVR induces reactive oxygen species (ROS) that leads to membrane lipid peroxidation and accumulation of toxic aldehydes, such as 4-hydroxy-2- nonenal (4-HNE). Both ALDH3A1 and ALDH1A1 detoxify 4-HNE, which has been implicated in the pathogenesis of several diseases including cataract and degenerative retinal disease. During the last funding period, we have made novel and significant discoveries regarding the protective role of ALDH3A1 and ALDH1A1 against ocular oxidative stress. We found that both enzymes protect against UVR- and 4-HNE-induced cellular toxicity, and that, at least ALDH3A1, may act as UVR filter protecting other enzymes from inactivation. Finally, and most importantly, we found that Aldh3a1(-/-) and Aldh1a1(-/-)/Aldh3a1(-/-) knockout mice develop anterior and posterior subcapsular cataracts early in life, whereas Aldh1a1(-/-) knockout animals develop cataracts later in life. These novel data support our working hypothesis that corneal ALDH3A1 and lens ALDH1A1 protect the eye against cataract formation via non- enzymatic (light filtering) and enzymatic (detoxification) functions.