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

描述：(改编自《调查者摘要》)可用数据 表明2%-3%的人类新生儿有临床可识别的 足月出生缺陷，这一比例增加到7-10%，如果 评估是在一岁时进行的。数据还表明，出生 缺陷是美国婴儿死亡的主要原因， 约占每五个婴儿死亡中的一个。 虽然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 暴露在其中扮演着重要的角色。这些研究还表明， 组织特异性细胞死亡是骨肉瘤发病机制中的常见事件。 发育毒物引起的异常发育。最近的工作来自 调查员实验室显示其中一把钥匙被激活 细胞凋亡途径的组成部分cspace-3直接相关。 在植入后早期小鼠中有这种组织特异性细胞死亡 胚胎。因此，本提案涉及两个相互关联的长期 目的：1)阐明分子信号转导途径。 发育毒物和2)阐明其作用机制(S) 发育毒物诱导组织特异性细胞死亡 植入小鼠胚胎。为了实现这些目标， 调查人员将调查以下具体目标：1)bc l-2 家庭成员调节发育毒物诱导的细胞死亡和 在神经上皮细胞敏感性/心脏细胞抵抗中发挥作用， 2)caspase-3的上游caspase被选中激活 发育毒物与组织特异性表达或激活 这些半胱氨酸天冬氨酸氨基转移酶参与神经上皮细胞敏感性/心脏细胞 抗性，3)caspase抑制剂决定胚胎对 发育毒物和促进神经上皮细胞 敏感性/心肌细胞抵抗力，以及4)线粒体在 发育性毒物诱导的细胞死亡和神经上皮细胞 敏感性/心脏细胞阻力。

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.