CELL DIFFERENTIATION AND RADIORESPONSE

哺乳动物细胞中辐射诱导的DNA损伤的修复通常 用体外培养的增殖细胞进行了研究。浩瀚无边 然而，大多数原位哺乳动物细胞是存在于有丝分裂后的 末端分化的一种状态。这项研究的长期目标是 项目是了解终末期分化的放射反应 细胞DNA损伤修复与细胞增殖的关系 细胞功能的维持。作为细胞分化的模型， 这些研究将集中在小鼠3T3-T前体脂肪细胞系统上。在……里面 这个系统，周期的3T3-T前体脂肪细胞暴露在人血浆中 导致其终末分化为成熟的脂肪细胞。我们有 研究表明，3T3-T前体脂肪细胞的分化伴随着 在全基因组分析时DNA修复能力的降低 单基因水平。现在的目标是了解DNA修复是如何 终末分化细胞缺陷对其功能的影响 对电离辐射的反应。因为基因组DNA的唯一目的是 末端分化的细胞是RNA转录，决定了 辐射引起的DNA损伤的后果主要包括 对脂肪细胞至关重要的特定基因的检测和转录 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，表达 暴露于空气中的即刻早期反应和次级反应基因 将对电离辐射进行调查。最后，我们将扩展这些 研究对小鼠前脂肪细胞的影响。 人神经母细胞瘤细胞系放射反应的分化。 拟议的研究将提供对辐射反应的洞察 分化的细胞，从而最终对一般 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.