CELL DEATH, CHALONES, AND CYTOTOXIC METABOLITES

胚胎癌调控机制的实验研究 细胞通过胚泡，囊胚液中的可溶性因子 一些胚胎性癌细胞的程序性细胞死亡 和内细胞团细胞，每个细胞都有分化成 滋养外胚层。从囊液中获得的初步数据 一种畸胎癌的腹水囊胚样胚体 提示细胞毒性多胺代谢物，由活动产生 在细胞程序性死亡过程中杀死目标细胞。 在这些实验中，选择性的影响变得明显 干细胞群体中的细胞死亡通常被认为是对 增殖，因此这些代谢物似乎产生类抑素 体外活性。从历史上看，Chone活动很难 与多胺毒性分开。因此，这一提议的假设是 细胞毒性多胺代谢物在程序化细胞过程中杀死细胞 死亡，从而在更新干细胞种群方面起到抑制作用 成年人。这项提议将检验这一假设的三个预测： 抗胺氧化酶抗体和多胺抗体将在某些地区共存 在胚胎和成人组织中的程序性细胞死亡，酶抑制剂 胺氧化酶可以防止细胞程序性死亡，而查尔酮则发挥作用。 它们通过多胺/胺氧化酶生物化学发挥作用。数据将 氧化损伤对选择性细胞死亡理解的影响 (包括药物和辐射诱导的)、形态和组织发生 胚胎，以及成体组织更新的异常。

During experiments on the mechanisms of regulation of embryonal carcinoma cells by the blastocyst, a soluble factor in blastocele fluid was identified that causes programmed cell death of some embryonal carcinoma and inner cell mass cells each with the potential to differentiate into trophectoderm. Preliminary data obtained with the cyst fluid from blastocyst-like embryoid bodies of the ascites form of a teratocarcinoma suggest that cytotoxic polyamine metabolites, generated by the activities of amine oxidases, kill the target cells during programmed cell death. During these experiments it became apparent that the effect of selective cell death on a stem cell population is often perceived as inhibition of proliferation, thus these metabolites appeared to produce chalone-like activity in vitro. Historically chalone activity has been difficult to separate from polyamine toxicity. Thus, the hypothesis of this proposal is that cytotoxic polyamine metabolites kill cells during programmed cell death and thereby act as a chalone in renewing stem cell populations of the adult. This proposal will test three predictions of the hypothesis: antibodies against amine oxidases and polyamines will co-localize in areas of programmed cell death in embryonic and adult tissues, enzyme inhibitors of amine oxidase will prevent programmed cell death, and chalones exert their effects via polyamine/amine oxidase biochemistry. The data will impact upon the understanding of selective cell death via oxidative damage (including drug- and radiation-induced), morpho- and histogenesis of the embryo, and aberrations of tissue renewal in the adult.