CELL CYCLE SPECIFIC CONTROL OF CELLULAR DIFFERENTIATION

细胞分化的细胞周期特异性控制

• 批准号: 3171357
• 负责人: ANDREW YEN
• 金额: $ 14.82万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-08-01 至 1994-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3171357
• 关键词: blood /lymphatic neoplasm; blood tests; cell cycle; cell differentiation; cell growth regulation; cell population study; cellular oncology; flow cytometry; gene expression; human subject; leukemia; mathematical model; mitogens; neoplasm /cancer genetics; neoplastic growth; nucleic acid hybridization; nucleic acid probes; oncogenes; retinoblastoma; synchronous cell division; tumor suppressor genes

The proposed studies continue to investigate the regulation of cell differentiation. The emphasis is on early cell physiological responses to inducers of terminal differentiation. The potential regulatory role of the RB (retinoblastoma) gene will be focused on. The insight so gained will hopefully promote the potential clinical use of differentiation inducing agents to treat hematopoietic neoplastic disease. Chemotherapy of leukemia has historically relied on relatively toxic agents to kill the tumor stem cells. An alternative is to use potentially less toxic agents to induce the terminal differentiation of leukemia cells, thereby arresting their proliferative activity and potentially restoring some of the differentiated cells that the patient is otherwise deprived of. To be able to optimally exploit this new treatment modality, it becomes necessary to know how various agents act at the cellular and molecular level to effect terminal differentiation of neoplastic cells. We will study this using a human leukemia cell line which differentiates in vitro. One target regulatory gene that has been little studied in this regard is the tumor suppressor genes, of which the RB retinoblastoma gene is the prototype. Expression of this gene has an apparent regulatory role in effecting terminal differentiation. Thus it becomes of interest to assessing tumor response and drug efficacy to determine how RB is regulated during induced terminal differentiation and how such agents affect its expression. Molecular mechanisms of differentiation induction therapy involving the RB tumor suppressor gene's role in differentiation will thus be studied. The working hypothesis is that the RB gene has a regulatory role in effecting terminal differentiation. Our preliminary evidence indicates that RB expression is down-regulated anteceding onset of terminal differentiation. Using a variety of agents to induce terminal differentiation of HL-60 human promyelocytic leukemia cells as an in vitro model, the role of the RB gene in effecting induced terminal differentiation will be studied by characterizing regulation of its expression and then experimentally manipulating that expression by molecular biological techniques to determine the consequences on cellular ability to differentiate. Because differentiation can be induced at will in these cells, they provide a powerful tool for investigating this process.

拟议的研究继续调查细胞的调节 差异化。 重点是早期细胞生理反应 终末分化诱导剂。 潜在的监管作用 我们将重点关注 RB（视网膜母细胞瘤）基因的变化。 洞察如此 所获得的成果有望促进其潜在的临床应用 治疗造血肿瘤的分化诱导剂 疾病。 白血病的化疗历来相对依赖于 杀死肿瘤干细胞的毒性剂。 另一种方法是使用 诱导终末分化的潜在毒性较小的试剂 白血病细胞，从而阻止其增殖活性 有可能恢复患者的一些分化细胞 否则被剥夺。 为了能够最佳地利用这一新的 治疗方式，有必要了解各种药物如何发挥作用 在细胞和分子水平上影响细胞的终末分化 肿瘤细胞。 我们将使用人类白血病细胞系来研究这一点 这在体外是有区别的。 一种靶标调控基因 在这方面研究很少的是肿瘤抑制基因，其中 RB是视网膜母细胞瘤基因的原型。 该基因的表达具有 在影响终末分化中具有明显的调节作用。 因此它 评估肿瘤反应和药物疗效变得有趣 确定 RB 在诱导终末分化过程中是如何受到调节的 这些试剂如何影响其表达。 分子机制 涉及 RB 肿瘤抑制因子的分化诱导治疗 因此将研究基因在分化中的作用。 工作中 假设 RB 基因在影响 终端分化。 我们的初步证据表明 RB 表达在终末期开始前下调 差异化。 使用多种药剂诱导终末期 HL-60人早幼粒细胞白血病细胞的分化 体外模型，RB基因在影响诱导终末期中的作用 将通过表征其调节来研究分化 表达式，然后通过实验操作该表达式 分子生物学技术来确定对细胞的影响 区分能力。因为可以随意诱导分化 在这些细胞中，它们为研究这一问题提供了强大的工具 过程。