BCL-2, ROS, AND CELL DEATH IN DEVELOPMENTAL TOXICITY

BCL-2、ROS 和发育毒性中的细胞死亡

• 批准号: 6518089
• 负责人: PHILIP E MIRKES
• 金额: $ 38.73万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-05-01 至 2004-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6518089
• 关键词: BCL2 gene /protein; apoptosis; cell death; cellular pathology; cyclophosphamide; cysteine endopeptidases; cytochrome c; developmental neurobiology; ecdysone; embryo /fetus tissue /cell culture; embryo /fetus toxicology; environmental toxicology; enzyme inhibitors; gene expression; genetic regulation; genetically modified animals; heart cell; hyperthermia; immunoprecipitation; laboratory mouse; mitochondria; oncogenes; polymerase chain reaction; teratogens; toxicant screening; western blottings; BCL2 gene /protein; apoptosis; cell death; cellular pathology; cyclophosphamide; cysteine endopeptidases; cytochrome c; developmental neurobiology; ecdysone; embryo /fetus tissue /cell culture; embryo /fetus toxicology; environmental toxicology; enzyme inhibitors; gene expression; genetic regulation; genetically modified animals; heart cell; hyperthermia; immunoprecipitation; laboratory mouse; mitochondria; oncogenes; polymerase chain reaction; teratogens; toxicant screening; western blottings

DESCRIPTION: (Adapted from the Investigator's Abstract) Available data indicates that 2-3% of all human neonates have clinically identifiable birth defects at term, this percentage increases to 7-10% if the assessment is made at one year of age. Data also indicate that birth defects constitute the leading cause of infant mortality in the U.S., accounting for approximately one out of every five infant deaths. Although the etiology of birth defects is often unknown, accumulated evidence from animal and human studies indicates that environmental exposures play a significant role. These studies also demonstrate that tissue specific cell death is a common event in the pathogenesis of developmental toxicant-induced abnormal development. Recent work from the investigator's laboratory shows that activation of one of the key components of the apoptotic pathway, caspace-3, is directly correlated with this tissue specific cell death in early post-implantation murine embryos. Thus, this proposal addresses two inter-related long-term objectives: 1) elucidation of the molecular pathways activated by developmental toxicants and 2) elucidation of the mechanism(s) by which developmental toxicants induce tissue-specific cell death in early post- implantation murine embryos. To accomplish these objectives, the investigators will investigate the following specific aims: 1) Bcl-2 family members regulate developmental toxicant-induced cell death and play a role in neuroepithelial cell sensitivity/heart cell resistance, 2) caspases "upstream" of caspase-3 are activated by selected developmental toxicants and tissue specific expression or activation of these caspases contribute to neuroepithelial cell sensitivity/heart cell resistance, 3) caspase inhibitors determine the embryo's response to developmental toxicants and contribute to neuroepithelial cell sensitivity/heart cell resistance, and 4) mitochondria play a role in developmental toxicant-induced cell death and in neuroepithelial cell sensitivity/heart cell resistance.

描述：（根据调查员的摘要进行了改编）可用数据 表明所有人类新生儿中有2-3％的临床可识别 学期出生缺陷，如果该百分比增加到7-10％ 评估是在一岁时进行的。数据还表明出生 缺陷构成了美国婴儿死亡率的主要原因， 每五名婴儿死亡中约有一个。 尽管出生缺陷的病因通常是未知的，但积累了 来自动物和人类研究的证据表明环境 暴露起着重要作用。这些研究还表明 组织特异性细胞死亡是在发病机理中的常见事件 发育毒物引起的异常发育。最近的工作 研究者的实验室表明，激活其中一项关键 凋亡途径的组件Caspace-3直接相关 在早期植入后鼠中，这种特异性细胞死亡 胚胎。因此，该提案解决了两个相互关联的长期 目的：1）阐明被激活的分子途径 发育有毒物质和2）阐明机制 发育有毒物质在早期诱导组织特异性细胞死亡 植入鼠类胚胎。为了实现这些目标， 调查人员将研究以下具体目的：1）BCL-2 家庭成员规范发育毒物引起的细胞死亡和 在神经上皮细胞灵敏度/心脏细胞耐药性中起作用， 2）caspase-3的caspase“上游”被选定激活 发育有毒物质和组织特异性表达或激活 这些胱天蛋白酶有助于神经上皮细胞灵敏度/心脏细胞 抗性，3）caspase抑制剂确定胚胎对 发育有毒物质并有助于神经上皮细胞 灵敏度/心脏细胞耐药性，4）线粒体在 发育毒物诱导的细胞死亡和神经上皮细胞 灵敏度/心脏细胞耐药性。