Regulation of Ocular Lens Development by Growth Factors

描述（由申请人提供）：保持对细胞的适当控制 生长和分化不仅在胚胎发育期间是至关重要的， 在动物的整个生命过程中， 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 在体内的作用还知之甚少。目镜透镜已经成为重要的 用于评估特定基因产物在调节中的作用的模型系统 生长和分化。近年来，我们和其他人，通过 通过基因打靶策略产生的转基因和突变小鼠的分析， 确定成视网膜细胞瘤易感蛋白，即，是一 透镜纤维细胞周期退出的重要调节因子 分化最近，我们还了解到pRB相关蛋白， p107和/或p130与pRB一起在细胞周期控制中起作用， 未分化上皮和纤维细胞分化期间。虽然 认为E2 F转录因子是pRB的关键靶点 蛋白质在透镜纤维分化过程中的具体作用，如果有的话， 单个E2 Fs在介导正常生长和分化中的作用 Rb失活的影响仍有待确定。pRB家族以外的因素 成员有助于调节细胞生长和分化， 透镜。我们最近的研究表明PDZ的一个迄今未被认识的作用 结构域蛋白，盘-大（DLG），果蝇中的肿瘤抑制因子， 调节上皮中的细胞增殖和结构完整性， 新分化的纤维细胞。在这次更新申请中，我们提出了四个 旨在进一步了解这些因素在调节 体内透镜细胞生长和分化。该提案的目的是： (1)确定PDZ结构域蛋白是否是调节细胞周期所必需的， 透镜上皮细胞结构;（2）确定pRB的作用 和pRB样蛋白在细胞周期控制中的作用， 透镜细胞的分化;（3）确定口袋蛋白-E2 F的作用 纤维分化过程中细胞周期控制的相互作用;（4）确定 如果pRB和/或pRB样蛋白在透镜中起分化因子的作用 分化这些研究的结果将有助于我们 了解肿瘤抑制蛋白如何调节细胞增殖， 以及破坏它们的功能如何有助于人类 如白内障等疾病。

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.