CELL CYCLE SPECIFIC CONTROL OF CELLULAR DIFFERENTIATION

细胞分化的细胞周期特异性控制

• 批准号: 3171358
• 负责人: ANDREW YEN
• 金额: $ 15.93万
• 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 1994-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3171358
• 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.

拟议中的研究继续调查细胞的调节 差异化。重点放在早期细胞生理反应上。 至顶端分化诱导剂。潜在的监管角色 将重点关注RB(视网膜母细胞瘤)基因的研究。这样的洞察 GAIN将有望促进其潜在的临床应用 造血肿瘤的分化诱导剂治疗 疾病。白血病的化疗历来依赖于相对 杀灭肿瘤干细胞的有毒物质。另一种选择是使用 潜在毒性较低的诱导剂诱导终末分化 白血病细胞，从而阻止其增殖活性和 有可能恢复患者体内某些分化的细胞 在其他方面被剥夺了。能够以最佳方式利用这一新的 治疗方式，有必要了解各种药物是如何发挥作用的 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 在体外分化。一个靶向调控基因一直是 在这方面研究较少的是肿瘤抑制基因，其中 Rb基因是视网膜母细胞瘤基因的原型。该基因的表达具有一种 在影响末端分化中起明显的调节作用。因此，它 评估肿瘤反应和药物疗效成为人们感兴趣的问题 确定Rb在诱导的末端分化过程中是如何调节的 这些因子如何影响它的表达。其分子机制研究进展 涉及Rb肿瘤抑制因子的诱导分化治疗 因此，我们将研究基因在分化中的作用。在工作中 假说是Rb基因在影响 末端分化。我们的初步证据表明Rb 在终末期发病前表达下调 差异化。使用多种试剂诱导终末 人早幼粒白血病细胞株HL-60诱导分化的实验研究 体外模型，Rb基因在影响诱导终末中的作用 将通过表征ITS的调节来研究分化 表达式，然后通过以下方式试验性地操作该表达式 确定对细胞的影响的分子生物学技术 区别对待的能力。因为分化可以随意诱导 在这些细胞中，它们为研究这一现象提供了一个强大的工具 进程。