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Molecular Pathological Aspects of Spontaneous Mouse Hereditary Keratoconus

自发性小鼠遗传性圆锥角膜的分子病理学方面

基本信息

批准号：
12470370
负责人：
TACHIBANA Masayoshi
金额：
$ 8.13万
依托单位：
NIIGATA UNIVERSITY (2003)Research Institute for Clinical Oncology, Saitama Cancer Center (2000-2002)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2003
项目状态：
已结题

项目摘要

Two lines of mouse with spontaneous hereditary keratoconus-like keratopathy were discovered in Saitama Cancer Center, which were named SKC (spontaneous keratoconus) and JKC (Japanese Keratoconus) mouse. SKC mouse was found in a closed colony of laboratory mouse, while JKC mouse was found in Japanese wild mice (Mus musculus molossinus). In this study, we characterized these mice and their corneas with special interests in their molecular-pathological and genetic aspects. Keratopathy of both SKC and JKC mice was inherited in an autosomal recessive manner, and linkage analyses in SKC mouse and JKC mouse linked each responsible or susceptible gene, to respectively, mouse chromosome 17 and 13.While keratopathy of JKC mice occurred in both genders that of SKC mice occurred selectively in males (keratopathy occurred only in extremely rare cases in female SKC mice). Interestingly, however, in female SKC mice the keratopathy appeared in many cases (66%) when androgen was given to them at approximately 4 weeks of age. These suggest that keratopathy of SKC mice is androgen-dependent (requires androgen to occur). In an effort to reveal the mechanism of this androgen-dependency, we examined the expression of androgen in mouse corneas. Expression of androgen receptors was detected in nuclei of various types of corneal cells as judged by immunohistochemistry, and expression of this receptor at RNA level was also detected by RT-PCR in mouse corneas. These suggest that androgen directly acts in corneal cells to cause keratopathy. In addition, we found that not only androgen receptor but also estrogen receptors of both a and b type are expressed in mouse corneas. further study revealed that sex steroid receptors are expressed in human corneas as well. Sex steroids may play an important role in development of keratoconus and other keratopthy in SKC mice and perhaps other mice or even in humans.

在崎玉癌症中心发现了两个自发性遗传性圆锥角膜样角膜病变小鼠系，分别命名为SKC(自发性圆锥角膜)和JKC(日本圆锥角膜)小鼠。SKC小鼠是在封闭的实验室小鼠群体中发现的，而JKC小鼠是在日本野鼠(Mus Musculus Molossinus)中发现的。在这项研究中，我们在分子病理学和遗传学方面对这些小鼠和它们的角膜进行了特殊的研究。SKC小鼠和JKC小鼠的角膜病变均为常染色体隐性遗传，SKC小鼠和JKC小鼠的连锁分析分别将致病基因和易感基因分别与小鼠17号和13号染色体连锁。而JKC小鼠的角膜病变在两性中均可发生，而SKC小鼠的角膜病变在雄性小鼠中选择性地发生(仅在雌性SKC小鼠中极少数发生)。然而，有趣的是，在雌性SKC小鼠中，当在大约4周大的时候给予雄激素时，许多病例(66%)出现了角膜病变。这表明SKC小鼠的角膜病变是雄激素依赖性的(需要雄激素才能发生)。为了揭示这种雄激素依赖的机制，我们检测了雄激素在小鼠角膜中的表达。免疫组织化学方法检测到不同类型角膜细胞中雄激素受体的表达，RT-PCR检测到该受体在小鼠角膜中的表达水平。这些结果表明，雄激素直接作用于角膜细胞，导致角膜病变。此外，我们还发现，不仅雄激素受体在小鼠角膜中表达，而且a和b型雌激素受体也在小鼠角膜中表达。进一步的研究发现，性类固醇受体也在人的角膜中表达。性类固醇可能在SKC小鼠和其他小鼠甚至人类的圆锥角膜和其他角膜病变的发展中发挥重要作用。