RADIOSENSITIVE TARGET IN THE EARLY MOUSE EMBRYO

早期小鼠胚胎中的辐射敏感目标

• 批准号: 2154083
• 负责人: LYNN M WILEY
• 金额: $ 17.41万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-03-01 至 1997-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2154083
• 关键词: antisense nucleic acid; cell growth regulation; chimeric proteins; chromosome aberrations; diagnosis design /evaluation; early embryonic stage; egg /ovum; embryo /fetus cell /tissue; embryo /fetus tissue /cell culture; genetic disorder diagnosis; genetically modified animals; growth factor receptors; in situ hybridization; insulinlike growth factor; ionizing radiation; laboratory mouse; mammalian embryology; oligonucleotides; prenatal growth disorder; radiation sensitivity; sperm; transforming growth factors

The mouse embryo chimera assay is a very sensitive test for detecting in vivo exposure of the mammalian germ cell to ionizing radiation. This exposure produces a competitive embryonic cell proliferation disadvantage that becomes expressed by the embryo from the exposed parent when challenged by cell-cell contact with a control embryo in an aggregation chimera. The detection limits of this assay for low-LET ionizing radiation (gamma or x rays) are between 0.005 Gy and 0.01 Gy for parental male irradiation and between 0.05 Gy and 0.15 Gy for parental female irradiation. During the current funding period we were successful in achieving our major objective, which was to determine whether the radiosensitive target for the assay was nuclear or extranuclear. The evidence we obtained strongly favors the hypothesis for a nuclear radiosensitive target in this competitive renewal application, we now wish to test hypotheses regarding the possible consequences of damage to this nuclear target and the predictive value of the chimera assay for transmitted embryonic effects using nuclear endpoints. Specific Aim 1 will test the hypothesis that this nuclear target consists of genes that affect cell proliferation rate through their impact on the efficiency of growth factor/receptor autocrine "loops". This hypothesis is based upon the known expression of several functional autocrine loops by the early embryo and on the accumulating evidence that growth factors, their receptors, associated signal transduction components and transcription factors are radiosensitive in a wide variety of cell lines and tissues. Specific Aims 2 and 3 are concerned with the predictive value of the chimera assay for embryonic effects resulting from parental exposures to ionizing radiation. As is the case for Specific Aim 1, the hypotheses tested here are predicated upon a nuclear radiosensitive target for the chimera assay. Specific Aim 2 will test the hypothesis that higher doses to the female germ line (0.3 Gy - 0.5 Gy of 137 Cs gamma radiation) will result in a temporal correlation between positive results of the chimera assay and the stages of oogenesis that transmit increases in developmental anomalies as reported in the literature (e.g., the specific locus test). Specific Aim 3 will test the hypothesis that there will be temporal correlations between positive results from the chimera assay and increases in frequencies of chromosomal aberrations detected in their germ cells by fluorescence in situ hybridization in males.

小鼠胚胎嵌合体试验是一种非常敏感的检测方法， 哺乳动物生殖细胞在体内暴露于电离辐射。这 暴露产生竞争性胚胎细胞增殖不利 当母体暴露在空气中时， 通过与聚集的对照胚胎的细胞-细胞接触来激发 奇美拉本试验对低LET电离辐射的检测限 （γ或x射线）在0.005戈伊和0.01戈伊之间 辐射，亲本雌性介于0.05戈伊和0.15戈伊之间 辐照在目前的融资期内，我们成功地 实现我们的主要目标，这是确定是否 用于测定的放射敏感靶是核或双核。的 我们获得的证据强烈支持核爆炸的假设。 在这次竞争性更新申请中，我们现在希望 为了测试关于损害的可能后果的假设， 核靶点和嵌合体检测的预测价值， 利用核终点传递胚胎效应。 具体目标1将检验这一核目标由 通过影响细胞增殖率的基因 生长因子/受体自分泌“环”的效率。这种假设是 基于几种功能性自分泌环的已知表达， 早期胚胎和越来越多的证据表明，生长因子， 它们的受体，相关的信号转导成分， 转录因子在多种细胞系中是放射敏感的 和纸巾。 具体目标2和3涉及以下方面的预测值： 用于亲代暴露于以下物质导致的胚胎效应的嵌合体测定 电离辐射与具体目标1一样，假设 这里测试的是基于核辐射敏感的目标， 嵌合体测定。具体目标2将检验以下假设： 对雌性生殖系（0.3戈伊- 0.5戈伊的137 Cs γ辐射）将 导致嵌合体的阳性结果之间的时间相关性 试验和卵子发生的阶段，传输增加发育 文献中报道的异常（例如，特定位点测试）。 具体目标3将检验以下假设： 嵌合体检测的阳性结果与 在他们的生殖细胞中检测到的染色体畸变的频率， 荧光原位杂交。