CELL CYCLE AND CELL DEATH STUDIES IN THE OCULAR LENS

晶状体中的细胞周期和细胞死亡研究

• 批准号: 2164930
• 负责人: Paul A. Overbeek
• 金额: $ 22.59万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-01 至 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2164930
• 关键词: cell cycle; cell cycle proteins; cell death; cell differentiation; cell growth regulation; crystallins; fiber cell; gene expression; genetically modified animals; immunocytochemistry; in situ hybridization; laboratory mouse; lens; neoplastic transformation; polymerase chain reaction; protein kinase; tumor antigens; tumor suppressor genes; viral carcinogenesis

The ocular lens provides an ideal system to study cell cycle regulation during terminal differentiation. The lens is composed of two cell types: the epithelial cells, which are capable of cellular proliferation, and the fiber cells, which are post-mitotic. I hypothesize that the differentiation of epithelial cells into fiber cells will cause alterations in activity of the genes that regulate the cell cycle. In order to help test this hypothesis, the alphaA-crystallin promoter will be used to direct lens-specific alterations in gene expression in transgenic mice. Transgenic and non-transgenic mice will be used to study two general classes of genes that are likely to be critical for cell cycle control during differentiation: tumor suppressors and cyclin-dependent kinases. The Specific Aims of this grant application are: l) to assess the role of the retinoblastoma (rb) protein in cell cycle control and terminal differentiation of lens fiber cells; 2) to assess the role of p53 in the induction of lens tumors by SV4O large T antigen; 3) to assay for changes in cyclin dependent kinases that accompany fiber cell differentiation; 4) to characterize the cell death that is induced by rb inactivation in fiber cells; and 5) to genetically reverse lens tumorigenesis induced by full-length T antigen. Our preliminary experiments have shown that expression of viral proteins that bind to rb and/or p53 can induce lens cell tumorigenesis or programmed cell death. Therefore, the cell cycle can be altered in lens cells with fascinating and unexpected consequences. The proposed studies should provide insights into cell cycle regulation in vivo, not only for the lens, but for other cells undergoing terminal differentiation or neoplastic transformation.

眼镜提供了研究细胞周期调节的理想系统 在终端分化过程中。 镜头由两种细胞类型组成： 上皮细胞，能够具有细胞增殖，并且 纤维细胞，后有丝分裂。 我假设 将上皮细胞分化为纤维细胞会导致 调节细胞周期的基因活性的改变。 在 为了帮助测试这一假设，α-晶状体启动子将是 用于引导转基因基因表达的透镜特异性改变 老鼠。 转基因和非转基因小鼠将用于研究两只 可能对细胞周期至关重要的一般基因类别 分化过程中的控制：肿瘤抑制剂和细胞周期蛋白依赖性 激酶。 该赠款申请的具体目的是：l）评估 视网膜母细胞瘤（RB）蛋白在细胞周期控制中的作用和 晶状体纤维细胞的末端分化； 2）评估p53的作用 在SV4O大抗原诱导镜头肿瘤中； 3）分析 伴随纤维细胞的细胞周期蛋白依赖激酶的变化 分化； 4）表征RB诱导的细胞死亡 纤维细胞失活； 5）遗传逆转镜头 全长T抗原诱导的肿瘤发生。 我们的初步 实验表明，与RB结合的病毒蛋白的表达 和/或p53可以诱导晶状体细胞肿瘤发生或程序性细胞死亡。 因此，可以在引人入胜的镜头细胞中改变细胞周期 和意外的后果。 拟议的研究应提供见解 在体内进行细胞周期调节，不仅用于镜头，而且针对其他镜头 经过末端分化或肿瘤转化的细胞。