CELL DIFFERENTIATION AND RADIORESPONSE

哺乳动物细胞中辐射诱导的DNA损伤的修复通常 通过使用体外生长的增殖细胞进行研究。 绝 然而，大多数原位哺乳动物细胞是有丝分裂后存在于细胞中的。 终末分化的状态。 本研究的长期目标是 项目是了解终末分化的放射反应， 细胞之间的关系，修复DNA损伤， 维持细胞功能。 作为细胞分化的模型， 这些研究将集中于鼠3 T3-T前脂肪细胞系统。 在 在该系统中，将循环的3 T3-T前脂肪细胞暴露于人血浆 导致其终末分化为成熟脂肪细胞。 我们有 表明3 T3-T前脂肪细胞的分化伴随着一个细胞周期， 在全基因组分析时DNA修复能力降低， 单基因水平。 现在的目标是了解DNA修复 终末分化细胞的缺陷影响其功能 对电离辐射的反应。 因为基因组DNA的唯一目的 终末分化的细胞是RNA转录，决定了 辐射引起的DNA损伤的后果主要包括： 脂肪细胞关键基因的测量和转录 功能 此外，由于细胞分化和DNA修复减少， 能力可能会影响基因的诱导和调控过程， 立即早期反应和二次反应基因在暴露于 将对电离辐射进行研究。 最后，我们将扩展这些 对小鼠前脂肪细胞的研究， 分化对人神经母细胞瘤细胞系的放射反应的影响。 拟议的研究将提供深入了解的放射反应， 分化的细胞，从而最终有助于一般 了解正常组织对辐射的反应。

The repair of radiation-induced DNA damage in mammalian cells has usually been investigated by using proliferating cells grown in vitro. The vast majority of mammalian cells in situ, however, are post-mitotic existing in a state of terminal differentiation. The long range goal of this research project is to understand the radioresponse of terminally differentiated cells with respect to the relationship between the repair of DNA damage and the maintenance of cell function. As a model for cellular differentiation, these studies will focus on the murine 3T3-T proadipocyte cell system. In this system, exposure of cycling 3T3-T proadipocytes to human plasma results in their terminal differentiation into mature adipocytes. We have shown that the differentiation of 3T3-T proadipocytes is accompanied by a reduction in DNA repair capacity when analyzed at the whole genome and single gene levels. The goal now is to understand how the DNA repair deficiencies of terminally differentiated cells impact on their functional response to ionizing radiation. Because the sole purpose of genomic DNA in a terminally differentiated cell is RNA transcription, determining the consequences of radiation-induced DNA damage will primarily involve measures of and the transcription of specific genes crucial for adipocyte function. In addition, because cell differentiation and reduced DNA repair capacity may affect gene induction and regulatory processes, the expression of immediate early response and secondary response genes after exposure to ionizing radiation will be investigated. Finally, we will extend these studies on murine proadipocytes to an investigation of the effects of differentiation on the radioresponse of a human neuroblastoma cell line. The proposed studies will provide insight into the radioresponse of differentiated cells, and thus ultimately contribute to the general understanding of normal tissue response to radiation.