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: 6629404
• 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 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6629404
• 关键词: acetazolamide; biological signal transduction; cadmium; cellular polarity; embryo /fetus tissue /cell culture; embryo /fetus toxicology; 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） 阐明胚胎对异生素暴露的立即反应是一个 可能对致畸风险的估计产生重大益处的研究方面。 我们认为这种压力/适应性反应的某些部分 据推测，跨物种的相似性会对发育产生负面影响 已知其中一些信号机制在不同物种之间是相同的。 我们之所以得出这个假说，是因为许多化学和物理现象 具有不同药效活性的药物会诱导相同的、非常局部的作用 肢体畸形，前肢后肢缺失， 主要发生在右侧，即轴后右前肢外指畸形。 此外，其中许多药物都是有据可查的人类致畸剂，例如 如丙戊酸、视黄酸和乙醇。 这个假定的原因/结果 适应性反应与局部肢体畸形之间的关系是 对探索非常有吸引力，因为我们知道发育信号 肢体在没有后指的情况下发育时发生改变的机制。 极化活性，后肢芽中胚层诱导极化的能力 当移植到宿主雏鸡翅膀的前缘时，肢体重复是 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。 我们已经证明这个活动 从暴露于乙酰唑胺的四肢中丢失。 在具体目标 1 中，我们将 检验镉暴露同样会减少极化的假设 小鼠肢芽的活动，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 肢芽细胞暴露后的适应性反应途径 乙酰唑胺或镉，两者均诱导右前肢轴后 特指。 我们将利用微阵列分析来检查压力 对致畸剂暴露的反应。 我们假设一个共同的适应性 会诱导对乙酰唑胺和镉的反应。 未来的研究将 检查这种适应性反应干扰的能力 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 对肢体形态发生或外源性反应或两者均重要的基因。