ALDOSE REDUCTASE AND DIABETIC EYE DISEASE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 糖尿病被认为是20岁至74岁的美国人新增失明病例的主要原因。与普通人群相比，糖尿病患者面临的失明风险增加了25倍。我们的长期目标是阐明糖尿病眼病的相关机制，以便制定预防或延缓糖尿病对眼睛的破坏性影响的策略。醛糖还原酶在糖尿病白内障和视网膜病变的发病机制中有一定的作用，但其机制尚不清楚。该项目的目标是确定糖尿病眼病的发生和发展是否受到醛酮还原酶水平的遗传操作的影响。具体目的之一将检验糖尿病白内障的形成不依赖于醛糖还原酶产生糖醇的假设。这将通过使用转基因小鼠来实现，转基因小鼠可以直接在晶状体中表达醛糖还原酶(催化葡萄糖转化为山梨醇)或小肠还原酶(不催化依赖葡萄糖的山梨醇合成)。转基因表达的后果将在有和没有诱发实验性糖尿病的情况下进行评估。转基因晶状体将被用于加速晶状体上皮细胞的凋亡和糖尿病引起的上皮细胞形态的改变。还将测量氧化应激的生化标记物。具体目标二将验证这样一种假设，即醛糖还原酶和相关的醛酮还原酶基因的缺失将预防糖尿病视网膜病变和白内障。在诱导实验性糖尿病后，视网膜血管细胞的形态和功能变化将在基因敲除和对照小鼠中进行评估。检测不同系基因靶向小鼠血管细胞的凋亡将揭示醛酮还原酶基因表达是否在糖尿病视网膜病变的发病机制中起作用。将对晶状体透明度进行类似的比较，以确定单个AKR基因对糖尿病白内障的影响。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Diabetes mellitus is recognized as a leading cause of new cases of blindness among Americans between the ages of 20 and 74. In comparison with the general population, diabetic patients face a 25-fold increased risk of blindness. Our long term objectives are to elucidate mechanisms involved in diabetic eye disease in order to develop strategies to prevent or delay the devastating effects of diabetes on the eye. Aldose reductase has been implicated in the pathogenesis of diabetic cataract and retinopathy, but we do not understand the mechanism. The goals of this project are to determine whether the onset and progression of diabetic eye disease is influenced by genetic manipulation of aldo-keto reductase enzyme levels. Specific aim one will test the hypothesis that diabetic cataract formation is not dependent on production of sugar alcohols by aldose reductase. This will be accomplished with the use of transgenic mice that direct lens expression of either aldose reductase, which catalyzes conversion of glucose to sorbitol, or small intestine reductase, which does not catalyze glucose-dependent sorbitol synthesis. Consequences of transgene expression will be assessed with and without induction of experimental diabetes. Transgenic lenses will be studied for accelerated lens epithelial cell apoptosis and diabetes-induced alterations of epithelial cell morphology. Biochemical markers of oxidative stress will also be measured. Specific aim two will test the hypothesis that deletion of genes for aldose reductase and related aldo-keto reductases will protect against diabetic retinopathy and cataract. Morphological and functional changes to retinal vascular cells following induction of experimental diabetes will be assessed in gene knockout and control mice. Measurement of apoptotic vascular cells in different lines of gene-targeted mice will reveal whether aldo-keto reductase gene expression contributes to the pathogenesis of diabetic retinopathy. Similar comparisons will be made for lens transparency to determine the influence of individual AKR genes on diabetic cataract.