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Exploration of pathogenesis of diabetic complications using transgenic mice and attempts of gene therapy

转基因小鼠糖尿病并发症发病机制探索及基因治疗尝试

基本信息

批准号：
14370073
负责人：
YAGIHASHI Soroku
金额：
$ 8.9万
依托单位：
Hirosaki University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2005
项目状态：
已结题

项目摘要

To explore the mechanisms of diabetic complications and to establish the direction for the prevention and treatment of them, we studied biochemical, physiological and pathological changes in microvessels and peripheral nerve tissues using recently developed transgenic animal models. In this study, we used transgenic mice overexpressing human aldose reductase (AR) and knockout mice that were deficient of AR to examine the role of polyol pathway. On the other hand, transgenic mice that overexpress receptor for advanced glycation endproducts (RAGE) were used to see the effects of RAGE overexpression in the endothelial cells on the development of diabetic complications. These mouse models were made diabetic by intravenous injection of streptozotocin and followed for 16 weeks. The diabetic AR mice exhibited marked depression of protein kinase C (PKC) activity in the nerve while PKC activity was contrariwise elevated in vascular tissues. These changes were due to reduced membrane expression … More of PKC-alpha in the nerve and increased membrane expression of PKC-beta in vascular tissues. These alterations were associated with significant functional and structural pathology in nerve and vessels in diabetic animals and not found in diabetic AR-knockout mice. Inhibitors for AR effectively prevented all the changes. Thus, it was concluded that AR plays a crucial role in the cause of diabetic complications and its inhibition is effective for the prevention and treatment. However, under very severe hyperglycemia, even AR knockout mice could not escape the pathological changes of diabetic complications and other mechanisms were thought to exert for tissue injury. As one possible mechanism, RAGE overexpression induced more severe tissue damage compared to control diabetic mice, thus suggesting the implication of AGE-RAGE interaction for the development of diabetic complications. The current series of studies clearly demonstrated the multiple factors implicating in the cause of diabetic complications and we consider that multi-facet directions for the prevention and treatment will be essential for the clinical applications. Less

为了探讨糖尿病并发症的发生机制，为糖尿病并发症的防治提供方向，我们利用新近建立的转基因动物模型，对糖尿病周围神经和微血管组织的生化、生理和病理变化进行了研究。在这项研究中，我们使用高表达人醛糖还原酶(AR)的转基因小鼠和AR缺失的基因敲除小鼠来研究多元醇途径的作用。另一方面，使用过表达晚期糖基化终产物受体(RAGE)的转基因小鼠来观察内皮细胞中RAGE过表达对糖尿病并发症发生的影响。通过静脉注射链脲佐菌素复制糖尿病小鼠模型，并追踪观察16周。糖尿病AR小鼠神经中蛋白激酶C(PKC)活性明显降低，而血管组织中PKC活性明显升高。这些变化是由于膜表达…减少所致神经中PKC-α表达增加，血管组织中PKC-β膜表达增加。这些改变与糖尿病动物神经和血管的显著功能和结构病理有关，而在糖尿病AR基因敲除小鼠中没有发现。AR的抑制剂有效地阻止了所有这些变化。因此，AR在糖尿病并发症的发生中起着重要作用，抑制AR对糖尿病并发症的防治是有效的。然而，在非常严重的高血糖状态下，即使AR基因敲除的小鼠也无法逃脱糖尿病并发症等被认为对组织损伤施加的机制的病理变化。作为一种可能的机制，RAGE过度表达导致了比对照组糖尿病小鼠更严重的组织损伤，从而提示年龄-RAGE交互作用在糖尿病并发症的发生发展中的意义。目前的一系列研究清楚地表明糖尿病并发症的原因涉及多方面的因素，我们认为多方面的预防和治疗方向将是临床应用的关键。较少