Mechanisms of lens growth regulation

描述（申请人提供）：老花眼和老年性白内障（ARC）是两种最常见的与年龄有关的眼部疾病，没有有效的方法来延缓或预防它们。晶状体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、离子和水分从周围代谢活跃的细胞运输到内部代谢不活跃的纤维的距离，这可能会阻碍晶状体的稳态，从而导致老年性白内障。目前尚不清楚为什么晶状体赤道上皮细胞继续增殖并分化为细长纤维细胞，即使在晶状体达到适当的尺寸后，可以将清晰的图像聚焦到视网膜上。在成熟的眼睛中，许多其他类型的细胞，包括角膜内皮细胞、视网膜神经元和视网膜色素上皮细胞，都不需要细胞增殖和分化来维持稳态或功能。也许在晶状体达到适当尺寸后，抑制晶状体尺寸的增加可以有效地维持晶状体的稳态，从而延缓老花眼和老年性白内障的发生。然而，由于缺乏适当的方法来选择性地阻止成熟晶状体生长而不影响早期晶状体形成，这种策略从未被测试过。目前对晶状体生长调控的认识主要来自对晶状体早期发育的研究。成熟晶状体发育完全后晶状体生长的调控机制研究甚少。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，在晶状体发育完全后，aA-crystallin Y118D突变选择性地抑制晶状体生长。突变体晶状体在断奶后生长急剧减少，并在8周时停止生长。我们假设功能获得的aA-crystallin 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，以减少和停止完全发育的晶状体的生长，这种选择性抑制取决于晶状体细胞中aA-crystallin Y118D突变蛋白的水平和/或功能的改变。本研究计划将验证这一假设，并阐明具有伴侣样活性增加的aA-crystallin Y118D突变蛋白如何调节晶状体上皮细胞的细胞和力学特性的分子基础。这一信息将有助于开发一种新的策略来抑制成熟晶状体的尺寸增加，从而预防老花眼和/或延缓与年龄有关的白内障。

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.