Mechanisms of lens growth regulation

晶状体生长调节机制

• 批准号: 8617846
• 负责人: Xiaohua Gong
• 金额: $ 30.09万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8617846
• 关键词: 3-Dimensional; Affect; Age; Aging; Apoptosis; Atomic Force Microscopy; Biological Assay; Birth; Bromodeoxyuridine; Cataract; Cell Differentiation process; Cell Proliferation; Cells; Cessation of life; Confocal Microscopy; Corneal Endothelium; Crystallins; Cultured Cells; Development; Disease; Elasticity; Embryo; Endothelial Cells; Epithelial Cells; Epithelium; Eye; Eye diseases; Fiber; Goals; Growth; Homeostasis; Image; Ions; Knock-out; Knowledge; Label; Life; Measures; Mechanics; Modeling; Molecular; Molecular Chaperones; Mutant Strains Mice; Mutation; Nutrient; Peripheral; Point Mutation; Presbyopia; Principal Investigator; Proliferating; Property; Proteins; Regulation; Research Project Grants; Research Proposals; Retina; Reverse Transcriptase Polymerase Chain Reaction; Structure; Structure of retinal pigment epithelium; Surface; System; TdT-Mediated dUTP Nick End Labeling Assay; Testing; Tetanus Helper Peptide; Water; Weaning; Western Blotting; age related; base; caspase-3; cell type; design; electron tomography; fiber cell; gain of function; in vitro activity; in vivo; lens; mutant; prevent; programs; public health relevance; retinal neuron

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.

描述（由申请人提供）：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部疾病，并且没有有效的方法来延迟或预防它们。在整个生命过程中连续的透镜生长不仅会增加透镜的硬度从而导致老花眼，而且会增加营养物质、离子和水从外周代谢活性细胞运输到内部代谢不活性纤维的距离，这可能阻碍透镜体内平衡从而导致年龄相关性白内障。还不知道为什么即使在透镜达到将清晰图像聚焦到视网膜上的适当尺寸之后，透镜赤道上皮细胞仍继续增殖并分化成伸长的纤维细胞。细胞增殖和分化对于维持许多其他细胞类型（包括成熟眼中的角膜内皮细胞、视网膜神经元和视网膜色素上皮细胞）的稳态或功能不是必需的。也许在透镜达到其适当尺寸后抑制透镜尺寸增加将有效地维持透镜体内平衡以延迟老花眼和年龄相关性白内障。然而，由于缺乏选择性地防止成熟透镜生长而不影响早期透镜形成的适当方法，这种策略从未被测试过。目前关于透镜生长调节的知识主要来自早期透镜发育的研究。透镜在成熟透镜完全发育后的生长规律很少被研究。因此，本计画的主要目的是研究透镜完全开发后的成长控制机制。我们最近发现α A-晶状体蛋白Y118 D突变在透镜完全发育后选择性抑制透镜生长。突变晶状体在断奶年龄后显示出显著降低的生长，并在8周龄时停止生长。我们假设功能获得性α A-晶状体蛋白Y118 D突变蛋白选择性抑制透镜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透镜的生长，并且这种选择性抑制依赖于透镜细胞中α A-晶状体蛋白Y118 D突变蛋白的改变的水平和/或功能。这项研究计划将测试这一假设，并阐明如何增加分子伴侣样活性的aA-晶状体蛋白Y118 D突变蛋白调节透镜上皮细胞的细胞和机械性能的分子基础。这些信息将有助于开发一种新的策略，以抑制成熟晶状体的尺寸增加，从而预防老花眼和/或延迟年龄相关性白内障。