Regulation of Ocular Lens Development by Growth Factors

描述(申请人提供)：保持对牢房的适当控制 生长和分化不仅在胚胎时期是至关重要的 在动物的整个生命过程中，当组织处于动态平衡时也会发育 和自我更新是长期生存所必需的。尽管它们很重要， 控制这些细胞过程的分子机制 在活体内，人们对此知之甚少。人工晶状体已经成为一种重要的 评估特定基因产物在调控中作用的模型系统 体内生长和分化。近年来，我们和其他人通过 基因打靶策略产生的转基因和突变小鼠的分析， 确定视网膜母细胞瘤易感蛋白是一种 晶状体纤维细胞中细胞周期退出的重要调节因子 差异化。最近，我们还了解到与PRB相关的蛋白质， P107和/或p130与pRb一起在细胞周期调控中发挥作用 未分化上皮和纤维细胞分化过程中。尽管它 认为E2F转录因子是pRb的关键靶点 蛋白质在晶状体纤维分化中的特殊作用，如果有的话， 个体E2F在调节正常生长分化中的作用 Rb失活的原因仍有待确定。PRB家族以外的其他因素 成员对细胞生长和分化的调节做出了贡献 镜头。我们最近的研究表明，到目前为止，自贸区的作用尚未被认识到。 DLG是果蝇的一种肿瘤抑制因子，在 调节上皮细胞的增殖和结构完整性 新分化的纤维细胞。在这次续签申请中，我们提出了四项 旨在加深我们对这些因素在调控中的作用的理解 晶状体细胞在体内的生长和分化。该建议的目的是： (1)确定是否需要PDZ结构域蛋白来调节细胞周期和 晶状体上皮中的上皮细胞结构；(2)确定pRb的作用 和pRb样蛋白在细胞周期控制中的未分化和 诱导晶状体细胞分化；(3)确定Pocket蛋白-E2F的作用 纤维分化过程中细胞周期调控的相互作用；(4)确定 如果pRb和/或pRb样蛋白在晶状体中起分化因子的作用 差异化。总之，这些研究的结果将有助于我们的 了解肿瘤抑制蛋白如何调节细胞增殖和 体内分化及其功能破坏对人类的影响 白内障等疾病。

DESCRIPTION (provided by applicant): Maintaining proper control over cell growth and differentiation is fundamentally important not only during embryonic development but also throughout the life of the animal when tissue homeostasis and self-renewal are required for long-term survival. Despite their importance, the molecular mechanisms through which these cellular processes are controlled in vivo are only poorly understood. The ocular lens has become an important model system for evaluating the roles of specific gene products in regulating growth and differentiation in vivo. In recent years, we and others, through the analysis of transgenic and mutant mice generated by gene targeting strategies, determined that the retinoblastoma susceptibility protein, i.e., is an essential regulator of cell cycle withdrawal during lens fiber cell differentiation. More recently, we also learned that the pRB-related proteins, p107 and/or p130, play a role with pRB in cell cycle control both in the undifferentiated epithelium and during fiber cell differentiation. Although it is thought that the E2F transcription factors are critical targets of pRB proteins during lens fiber differentiation, the specific roles, if any, for individual E2Fs in mediating normal growth and differentiation or the effects of Rb inactivation, remain to be determined. Factors other than the pRB family members contribute to the regulation of cell growth and differentiation in the lens. Our recent studies suggest a heretofore unrecognized role of the PDZ domain proteins, discs-large (DLG), a tumor suppressor in Drosophila, in regulating cell proliferation and structural integrity in the epithelium and newly differentiating fiber cells. In this renewal application, we propose four aims to further our understanding of the roles of these factors in regulating lens cell growth and differentiation in vivo. The aims of the proposal are to: (1) determine if PDZ domain proteins are required for regulating cell cycle and epithelial cell structure in the lens epithelium; (2) determine the role of pRB and pRB-like proteins in cell cycle control in the undifferentiated and differentiating cells of the lens; (3) determine the role of pocket protein-E2F interactions in cell cycle control during fiber differentiation; (4) determine if pRB and/or pRB-like proteins play a role as a differentiation factor in lens differentiation. Together, the results of these studies will contribute to our understanding of how tumor suppressor proteins regulate cell proliferation and differentiation in vivo and how disrupting their function contributes to human disease such as cataracts.