The role of Crim-1 in lens development and eye disease.

Crim-1 在晶状体发育和眼部疾病中的作用。

• 批准号: nhmrc : 142977
• 负责人: Prof Frank Lovicu
• 金额: $ 13.1万
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2001
• 资助国家: 澳大利亚
• 起止时间: 2001-01-01 至 2003-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/role-crim-1-eye-disease/78482
• 关键词: role; Crim; lens; development; eye

We have recently isolated a novel gene (Crim1) and shown it to be strongly expressed during eye development. Its protein structure indicates that it may act to regulate the activities of two growth factor families, the TGF superfamily and the insulin-IGFs. These growth factors effect the behaviour of many cell types that influence events in normal and pathological development. For example in the eye lens, TGF 1 can induce cataractous changes in epithelial cells and early differentiating fibres; however, TGF signalling appears to be required for events in late stages of fibre cell maturation. Cataract is the leading cause of blindness and arises when lens cell architecture is disrupted and-or proteins aggregate abnormally. In humans, following ocular trauma, eye surgery, or in association with other diseases, cataracts can develop. These cataracts feature the development of subcapsular fibrotic plaques which obscure vision. We have shown that lenses cultured in the presence of TGF can mimic production of these plaques suggesting that these cataracts result from inappropriate activation of TGF . TGF is expressed in the lens and is abundant in the ocular media that bathes the lens. Thus, it appears that complex regulation of TGF bioavailability is required; epithelial cells and young fibre cells need to be protected from its cataractogenic effects, whereas older fibres require TGF signalling for maturation and-or survival. The expression pattern of Crim1 in the lens is consistent with it having a key role in inhibiting TGF in the lens. Thus, we hypothesise that Crim1 plays important roles in the lens, possibly via the modulation of members of the TGF superfamily and insulin-IGFs. We predict that Crim1 acts to maintain the lens epithelial phenotype and facilitate events in early fibre differentiation. If so, this may have implications for devising molecular strategies for preventing or slowing diseases, such as the various forms of human cataract.

我们最近分离出一种新基因（Crim1），并表明它在眼睛发育过程中强烈表达。其蛋白质结构表明它可能调节两个生长因子家族（TGF 超家族和胰岛素-IGF）的活性。这些生长因子影响许多细胞类型的行为，从而影响正常和病理发育的事件。例如，在眼睛晶状体中，TGF-1可以诱导上皮细胞和早期分化纤维的白内障变化；然而，TGF 信号传导似乎是纤维细胞成熟后期事件所必需的。白内障是导致失明的主要原因，当晶状体细胞结构被破坏和/或蛋白质异常聚集时就会出现白内障。在人类中，在眼外伤、眼科手术或与其他疾病相关后，可能会出现白内障。这些白内障的特点是出现囊下纤维化斑块，从而遮挡视力。我们已经证明，在存在 TGF 的情况下培养的晶状体可以模拟这些斑块的产生，表明这些白内障是由 TGF 的不适当激活引起的。 TGF 在晶状体中表达，并且在沐浴晶状体的眼介质中含量丰富。因此，看来需要对 TGF 生物利用度进行复杂的调节；上皮细胞和年轻的纤维细胞需要受到保护，免受其致白内障的影响，而较老的纤维则需要 TGF 信号传导来实现成熟和/或存活。 Crim1在晶状体中的表达模式与其在抑制晶状体中TGF的关键作用一致。因此，我们假设 Crim1 在晶状体中发挥重要作用，可能是通过调节 TGF 超家族成员和胰岛素-IGF 来实现的。我们预测 Crim1 的作用是维持晶状体上皮表型并促进早期纤维分化。如果是这样，这可能会对设计预防或减缓疾病（例如各种形式的人类白内障）的分子策略产生影响。