CELL DEATH, CHALONES, AND CYTOTOXIC METABOLITES

细胞死亡、查龙和细胞毒性代谢物

• 批准号: 3196033
• 负责人: RALPH E PARCHMENT
• 金额: $ 20.75万
• 依托单位: CANCER PREVENTION INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-12-01 至 1994-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3196033
• 关键词: affinity chromatography; amine oxidase (copper); amine oxidase (flavin); aminoacid inhibitor; blastema; cell death; cytotoxicity; enzyme mechanism; hematopoietic stem cells; high performance liquid chromatography; immunocytochemistry; keratinocyte; laboratory mouse; laboratory rabbit; newborn animals; polyamines; teratoma; tissue /cell culture

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.

在胚胎癌调控机制的实验中， 细胞的囊胚，囊胚液中的可溶性因子， 发现导致一些胚胎癌的程序性细胞死亡 和内细胞团细胞，每个细胞都有分化成 滋养外胚层 从以下几种囊液中获得的初步数据： 腹水型畸胎癌的胚泡样胚状体 表明细胞毒性多胺代谢物，产生的活动， 在程序性细胞死亡过程中杀死靶细胞。 在这些实验中，很明显，选择性的效果 干细胞群体的细胞死亡通常被认为是对细胞增殖的抑制。 增殖，因此这些代谢产物似乎产生了类似于 体外活性 从历史上看， 与多胺毒性分开。 因此，该提议的假设是 细胞毒性多胺代谢物在程序化细胞中杀死细胞， 死亡，从而作为一个在更新干细胞群体的查尔酮， 成年人了 本提案将检验该假设的三个预测： 抗胺氧化酶和多胺的抗体将共同定位于 胚胎和成人组织中程序性细胞死亡的酶抑制剂 胺氧化酶将防止程序性细胞死亡， 它们的作用通过多胺/胺氧化酶生物化学。 数据将 对理解氧化损伤导致的选择性细胞死亡的影响 （包括药物和辐射诱导的），形态和组织发生的 胚胎，和成人组织更新的畸变。