ALDOSE REDUCTASE AND DIABETIC EYE DISEASE

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 研究中心，而研究中心不一定是研究者所在的机构。 糖尿病被认为是20至74岁美国人新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机制，以制定预防或延迟糖尿病对眼睛的破坏性影响的策略。醛糖还原酶参与了糖尿病性白内障和视网膜病变的发病机制，但其具体机制尚不清楚。本项目的目标是确定糖尿病性眼病的发生和进展是否受到醛酮还原酶水平的遗传操作的影响。具体目标一将检验糖尿病性白内障的形成不依赖于由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，所述转基因小鼠指导透镜中催化葡萄糖转化为山梨醇的醛糖还原酶或不催化葡萄糖依赖性山梨醇合成的小肠还原酶的表达。将在诱导和不诱导实验性糖尿病的情况下评估转基因表达的后果。将研究转基因晶状体的加速透镜上皮细胞凋亡和糖尿病诱导的上皮细胞形态学改变。还将测量氧化应激的生化标志物。具体目标二将检验缺失醛糖还原酶和相关醛酮还原酶基因将防止糖尿病视网膜病变和白内障的假设。将在基因敲除小鼠和对照小鼠中评估诱导实验性糖尿病后视网膜血管细胞的形态和功能变化。在不同品系的基因靶向小鼠中测量凋亡的血管细胞将揭示醛酮还原酶基因表达是否有助于糖尿病视网膜病变的发病机制。将对透镜透明度进行类似的比较，以确定单个AKR基因对糖尿病性白内障的影响。

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.