Mechanisms of lens growth regulation

描述(申请人提供)：老花眼和年龄相关性白内障(ARC)是两种最常见的年龄相关性眼病，目前还没有有效的方法来延缓或预防它们。晶状体在一生中的持续生长不仅会增加晶状体的硬度，导致老花眼，还会增加营养物质、离子和水从外周代谢活跃的细胞到内部代谢不活跃的纤维的运输距离，这可能会阻碍晶状体的动态平衡，从而导致老年性白内障。目前尚不清楚为什么在晶状体达到合适的大小以将清晰的图像聚焦到视网膜上后，晶状体赤道上皮细胞仍继续增殖并分化为细长的纤维细胞。在成熟眼中，细胞增殖和分化不是维持包括角膜内皮细胞、视网膜神经元和视网膜色素上皮细胞在内的许多其他细胞类型的稳态或功能所必需的。也许在晶状体达到合适的大小后抑制晶状体大小的增加将有效地维持晶状体的动态平衡，从而延缓老花眼和老年性白内障。然而，由于缺乏适当的方法来选择性地防止成熟晶状体生长而不影响早期晶状体形成，这样的策略从未被测试过。目前有关晶状体生长调节的知识主要来源于对晶状体早期发育的研究。成熟晶状体完全显影后晶状体生长的调控研究很少。因此，本项目的主要目标是研究晶状体完全发育后的生长控制机制。我们最近发现，在晶状体完全发育后，AA-晶体蛋白Y118D突变选择性地抑制晶状体的生长。突变晶状体在断奶后生长急剧减慢，在8周龄时停止生长。我们推测，功能获得的AA-晶状体蛋白Y118D突变蛋白选择性地抑制晶状体上皮细胞的增殖和分化和/或新分化的纤维细胞的伸长，从而减少和停止完全发育的晶状体的生长，这种选择性抑制依赖于晶状体细胞中AA-晶状体蛋白Y118D突变蛋白的水平和/或功能的改变。这项研究计划将检验这一假说，并阐明具有伴侣样活性的AA-晶体蛋白Y118D突变蛋白如何调节晶状体上皮细胞的细胞和机械特性的分子基础。这一信息将有助于开发一种新的策略，以抑制成熟晶状体尺寸的增加，从而预防老花眼和/或延缓与年龄相关的白内障。

DESCRIPTION (provided by applicant): Presbyopia and age-related cataracts (ARC) are two of the most common age-related ocular disorders, and there is no effective way to delay or prevent them. Continuous lens growth throughout life not only will increase the stiffness of lens to cause presbyopia but will also increase the distance for transport of nutrients, ions and water from peripheral metabolically active cells into interior metabolically inactive fibers, which likely impedes lens homeostasis to contribute to age-related cataract. It is unknown why lens equatorial epithelial cells continue to proliferate and differentiate into elongating fiber cells even after the lens reaches the appropriate size for focusing clear images onto the retina. Cell proliferation and differentiation are not required for maintaining the homeostasis or function of many other cell types including corneal endothelial cells, retinal neurons and retinal pigment epithelial cells in a mature eye. Perhaps inhibiting lens size increase after the lens reaches its appropriate size will effectively maintain lens homeostasis to delay presbyopia and age-related cataracts. However, such a strategy has never been tested due to a lack of appropriate way to selectively prevent mature lens growth without affecting early lens formation. Current knowledge about lens growth regulation is mainly from studies of early lens development. The regulation of lens growth in a mature lens after it is fully developed has been rarely studied. Thus, the primary goal of this project is to investigate the growth control mechanisms after the lens is fully developed. We have recently found that the aA-crystallin Y118D mutation selectively inhibits lens growth after the lens is fully developed. Mutant lenses display drastically reduced growth after weaning age and stop growing at the age of 8 weeks. We hypothesize that the gain-of-function aA-crystallin Y118D mutant protein selectively inhibits the proliferation and differentiation of lens epithelial cells and/or the elongation of newly differentiated fiber cells to reduce and stop the growth of a fully developed lens, and that such a selective inhibition depends on an altered level and/or function of aA-crystallin Y118D mutant proteins in lens cells. This research proposal will test this hypothesis and elucidate the molecular basis for how aA-crystallin Y118D mutant proteins with increased chaperone-like activity regulate the cellular and mechanical properties of lens epithelial cells. This information will be useful for developing a new strategy to inhibit size increase in mature lenses that may prevent presbyopia and/or delay age-related cataracts.