Microarray Analysis of Limb Bud Reaction to Teratogen E*

肢芽对致畸剂 E* 反应的微阵列分析

• 批准号: 6501361
• 负责人: WILLIAM J SCOTT
• 金额: $ 14.8万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-15 至 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6501361
• 关键词: acetazolamide; biological signal transduction; cadmium; cellular polarity; embryo /fetus tissue /cell culture; embryo /fetus toxicology; embryology; environmental exposure; functional /structural genomics; gene expression; histochemistry /cytochemistry; histogenesis; in situ hybridization; laboratory mouse; limbs; mesoderm; microarray technology; mutagens; polymerase chain reaction; skeletal disorder; teratogens; toxin; vertebrate embryology

DESCRIPTION (provided by applicant) Eludication of the immediate response of embryos to xenobiotic exposure is an aspect of research that could yield significant benefit to the estimation of teratogenic risk. We contend that some part of this stress/adaptive response which is presumable similar across species can negatively impact developmental signaling mechanisms some of which are known to be the same across species. We were led to this hypothesis by the fact that many chemical and physical agents with diverse pharmacodynamic activities induce the same, very localized limb malformation, absence of posterior digits from the forelimb, predominantly on the right side i.e., postaxial right forelimb ectrodactyly. Moreover, a number of these agents are well documented human teratogens such as valproic acid, retinoic acid, and ethanol. This putative cause/effect relationship between an adaptive response and a localized limb malformation is very attractive for exploration because we know a developmental signaling mechanism that is altered in the limb as it develops without posterior digits. Polarizing activity, the ability of posterior limb bud mesoderm to induce a limb duplication when grafted to the anterior margin of a host chick wing, is widely accepted as the basis of anterior/posterior (A/P) patterning of the limb across many species including humans. We have shown that this activity is lost from acetazolamide exposed muring limbs. In Specific Aim 1, we will test the hypothesis that cadmium exposure similarly reduces polarizing activity of the murine limb bud and will examine the consequenes on gene expression patterns in the limb. In Specific Aim 2, we propose to elucidate the adaptive response pathway of limb bud cells after exposure to acetazolamide or cadmium, both of which induce postaxial right forelimb extrodactyly. We will utilize microarray analysis to examine the stress response to teratogen exposures. We hypothesize that a common adaptive response to acetazolamide and cadmium will be induced. Future studies will examine the capability of such an adaptive response to interfere with polarazing activity, thereby leading to congenital malformation. A very exciting additional benefit will be the discovery and identification of new genes important in limb morphogenesis or xenobiotic response or both.

描述（由申请人提供） 胚胎对外源性暴露的即时反应的洗脱是一个 研究的一个方面，可以产生重大利益的估计， 致畸风险。 我们认为这种压力/适应性反应的一部分 这在物种之间是相似的，可能会对发育产生负面影响。 信号机制，其中一些已知是跨物种相同的。 我们之所以提出这个假设，是因为许多化学和物理物质 具有不同药效学活性的药物诱导相同的、非常局部的 四肢畸形，前肢没有后趾， 主要在右侧即，轴后右前肢缺指。 此外，这些药剂中的一些是有据可查的人类致畸剂， 如丙戊酸、视黄酸和乙醇。 这种假定的因果关系 适应性反应和局部肢体畸形之间的关系是 因为我们知道一种发育信号 在没有后趾的肢体发育过程中发生改变的机制。 极化活性，后肢芽中胚层诱导分化的能力， 当移植到宿主鸡翅膀的前缘时， 被广泛接受为前/后（A/P）模式的基础。 包括人类在内的许多物种的肢体。 我们已经证明， 是从乙酰唑胺暴露的四肢中丢失的。 具体目标1： 测试镉暴露类似地降低极化的假设 活动的小鼠肢芽，并将检查基因的后果 肢体的表达模式 在具体目标2中，我们建议阐明 肢体芽细胞暴露后的适应性反应途径 乙酰唑胺或镉，这两种药物均诱导右前肢轴后 外指畸形 我们将利用微阵列分析来检查压力 对致畸剂暴露的反应 我们假设一种常见的适应性 将诱导对乙酰唑胺和镉的反应。 未来的研究将 研究这种适应性反应干扰 极化活动，从而导致先天畸形。 一个非常 令人兴奋的额外好处将是发现和识别新的 在肢体形态发生或异生物反应或两者中重要的基因。