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Functional analysis of endoplasmic reticulum stress-induced genes, NDRG1 and HERPUD1

内质网应激诱导基因NDRG1和HERPUD1的功能分析

基本信息

批准号：
15570107
负责人：
MIYATA Toshiyuki
金额：
$ 2.37万
依托单位：
NATIONAL CARDIO VA SCULAR CENTER, RESEARCH INSTITUTE
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

Ndrg1 is an intracellular protein that is induced under a number of stress and pathological conditions, and it is thought to be associated with cell growth and differentiation. Recently, human NDRG1 was identified as a gene responsible for hereditary motor and sensory neuropathy-Lom (classified as Charcot-Mairie-Tooth disease type 4D), which is characterized by early-onset peripheral neuropathy. In this study, we generated mice lacking Ndrg1 to analyze its function. Histrogical analysis showed that the sciatic nerve of Ndrg1-defident mice degenerated with demyelination at about 5 weeks of age. Ndrg1-deficient mice showed muscle weakness, especially in the hind limbs, but complicated motor skills were retained. In wild-type mice, NDRG1 was abundantly expressed in the cytoplasm of Schwann cells rather than the myelin sheath. These results indicate that NDRG1 deficiency leads to Schwann cell dysfunction, suggesting that NDRG1 is essential for maintenance of the myelin sheaths in peripheral nerves.Herp has been isolated as a gene upregulated by atherogenic substance, homocysteine. To investigate the Herp function, we analyzed the phenotypes of Herp-null mice. The blood glucose levels were measured before and after intraperitoneal injection of glucose in Herp-null and wild-type mice. Focal cerebral ischemia was induced in these mice, and developments of cerebral infarction were compared. Herp-null mice were born normally, and exhibited no significant abnormalities. Although their fasting blood glucose levels were normal, the recovery speed after glucose load was moderately impaired. Since the response to insulin was normal, Herp may affect insulin production of pancreatic cells. The volumes of cerebral infarction in Herp-null mice were significantly larger than those in wild-type mice, indicating that Herp protects the brain under ischemia. Herp seems nonessential in normal conditions, but may play a protective role under some critical conditions.

ndrg 1是一种细胞内蛋白，在许多应激和病理条件下被诱导，并且被认为与细胞生长和分化相关。最近，人类NDRG 1被鉴定为负责遗传性运动和感觉神经病-Lom（被分类为Charcot-Mairie-Tooth疾病4D型）的基因，其特征在于早发性周围神经病。在这项研究中，我们产生了Ndrg 1缺乏的小鼠，以分析其功能。组织学分析显示，在约5周龄时，Ndrg 1缺陷小鼠的坐骨神经变性并伴有脱髓鞘。ndrg 1缺陷小鼠表现出肌肉无力，特别是在后肢，但复杂的运动技能保留。在野生型小鼠中，NDRG 1在雪旺细胞的细胞质中而不是髓鞘中大量表达。这些结果表明，NDRG 1缺陷导致雪旺细胞功能障碍，这表明NDRG 1是必不可少的维持髓鞘在周围神经。Herp已被分离为一个基因上调的致动脉粥样硬化物质，同型半胱氨酸。为了研究Herp功能，我们分析了Herp无效小鼠的表型。在腹膜内注射葡萄糖之前和之后，在Herp-null和野生型小鼠中测量血糖水平。在这些小鼠中诱导局灶性脑缺血，并比较脑梗死的发展。无疱疹病毒的小鼠出生正常，没有表现出显着的异常。虽然他们的空腹血糖水平正常，但葡萄糖负荷后的恢复速度中度受损。由于对胰岛素的反应是正常的，因此Herp可能影响胰腺细胞的胰岛素产生。Herp基因敲除小鼠的脑梗死体积明显大于野生型小鼠，表明Herp在缺血情况下保护脑。疱疹病毒在正常情况下似乎是不必要的，但在某些危急情况下可能起保护作用。