PHARMACOLOGY OF OCULAR COMPLICATIONS

眼部并发症的药理学

• 批准号: 6106805
• 负责人: PETER F KADOR
• 金额: --
• 依托单位: NATIONAL EYE INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6106805
• 关键词: affinity labeling; aldehyde reductase; chemical synthesis; computer simulation; diabetes mellitus; diabetic cataract; diabetic ophthalmopathy; diabetic retinopathy; disease /disorder prevention /control; dogs; enzyme activity; eye pharmacology; galactosemias; human tissue; laboratory rat; magnetic resonance imaging; medical complication; noninvasive diagnosis; nuclear magnetic resonance spectroscopy; oxidoreductase inhibitor

Diabetes is a rapidly increasing public health problem and the long-term complications such as neuropathy, nephropathy, microangiopathy, retinopathy and cataract associated with diabetes result in loss of vision, decreased quality of life, loss of limbs and motor function and increased mortality. Ocular diabetic complications include cataract, keratopathy and retinopathy. Blindness due to retinopathy is the leading cause of blindness in of adults industrialized countries, and diabetics undergo cataract surgery more often than non-diabetics. Studies conducted over the last 30 years have established a clear link between the excess accumulation of intracellular sorbitol levels and the onset of diabetic complications. Sorbitol is a sugar alcohol formed from glucose by the enzyme aldose reductase (AR). We have discovered that mammalian tissues contain an intrinsic aldose reductase inhibitor (IARI). The discovery of an IARI is significant because this represents a new class of nontoxic (or significantly less toxic) inhibitor. Studies indicate that the IARI is a heat-stable compound which inhibits aldose reductase in apparently the pico- to nanomolar range. Its molecular weight appears to be less than 1,000 and evidence suggests that it is a small polypeptide. In vitro lens culture studies with partially purified IARI indicate that this compound can cross membranes to inhibit the intralenticular production of sorbitol. Preliminary rat studies also indicate that this IARI is active in vivo. When the partially purified extract containing the IARI from bovine lenses was injected intraperitoneally into 24 hr galactose-fed rats, galactitol formation was inhibited by 94 % in the three rats receiving ca. 0.3 mL injection of extract and 54% in the rat receiving ca. 0.1 mL injection. Estimating that less than 0.1% of the material represents the tight-binding inhibitor, the injected level was under 6 ?g/kg. Studies are also being conducted on the pathophysiological mechanism of how aldose reductase initiates diabetic complications. Since no sequence information on the enzymes of the polyol pathway in the dog is available for basic molecular biological studies, canine aldose reductase, aldehyde reductase and sorbitol dehydrogenase have been cloned and sequenced. In addition, to develop new methods of inhibition of aldose reductase, a number of antisense oligomers to suppress human and rat AR gene expression in cell cultures have been designed and screened. Magnetic resonance imaging studies are also being conducted to determine if aldose reductase initiates human sugar cataracts. Using the noninvasive tool of magnetization transfer contrast (MTC) enhanced magnetic resonance imaging (MRI), we have obtained high contrast images of the eyes of galactose-fed dogs that indicate that osmotic changes linked to aldose reductase occur in the lenses of these dogs during cataract formation. This technique is now being applied to a clinical setting using normal volunteers ranging from 28 to 72 years in age. Preliminary studies indicate that the high contrast images obtained by MTC-MRI are a good tool for clinically investigating cataractous changes.

糖尿病是一种快速增长的公共健康 问题和长期的并发症，如神经病， 肾病、微血管病变、视网膜病变和白内障 糖尿病会导致视力丧失，生活质量下降，丧失 肢体和运动功能下降，死亡率增加。眼球 糖尿病并发症包括白内障、角膜病变和 视网膜病变。视网膜病变导致的失明是导致 工业化国家成年人失明，糖尿病患者经历 白内障手术比非糖尿病患者更多。进行的研究 在过去的30年里建立了明确的联系 细胞内山梨醇水平的过度积聚与 糖尿病并发症。山梨醇是一种糖醇，由 葡萄糖是由醛糖还原酶(AR)催化的。我们发现 哺乳动物组织中含有一种固有的醛糖还原酶 抑制剂(IARI)。IARI的发现意义重大，因为 这代表了一种新的无毒(或毒性显著降低) 抑制剂。研究表明，IARI是一种热稳定的化合物 它明显抑制微微到纳米分子中的醛糖还原酶 射程。它的相对分子质量似乎不到1000， 有证据表明，它是一种小分子多肽。晶状体体外培养 用部分纯化的IARI进行的研究表明，这种化合物可以 交叉膜以抑制晶状体内产生 山梨醇。初步的老鼠研究也表明，这种IARI是活跃的 在活体内。当含有IARI的部分纯化提取物 从牛晶状体中提取的蛋白质注射到24小时内 喂食半乳糖的大鼠，半乳糖醇的形成被抑制了94% 三只大鼠接受约0.3毫升的提取物注射，其中54% 大鼠接受约0.1毫升的注射。估计只有不到0.1%的 该材料代表紧密结合的抑制剂，即注入水平 低于6g/kg。此外，当局亦正就 醛糖还原酶启动的病理生理机制 糖尿病并发症。由于没有关于 狗体内的多元醇途径的酶是基本可用的 分子生物学研究，犬醛糖还原酶，醛 还原酶和山梨醇脱氢酶已被克隆并 已排序。此外，开发新的方法来抑制 醛糖还原酶，抑制多个反义寡聚体 人和大鼠AR基因在细胞培养中的表达 设计和筛选。磁共振成像研究是 也被用来确定醛糖还原酶是否启动 人类糖性白内障。使用非侵入性磁化工具 传递对比(MTC)增强磁共振成像 (核磁共振)，我们已经获得了高对比度的眼睛图像 喂食半乳糖的狗表明渗透性变化与 在白内障期间，这些狗的晶状体中存在醛糖还原酶 队形。这项技术现在正在临床环境中应用。 受试者年龄从28岁到72岁不等。 初步研究表明，获得的高对比度图像 MTC-MRI是临床研究的良好工具 白内障的变化。