Microarray Analysis of Limb Bud Reaction to Teratogen E*

描述(由申请人提供) 胚胎对异种生物暴露的即时反应是一种 可对估计致畸风险产生重大益处的研究方面。我们认为，这种压力/适应性反应的一部分 据推测，不同物种之间的相似可能会对发育产生负面影响 其中一些信号机制已知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因素 具有不同药效学活性的药物会产生相同的、非常局部化的 四肢畸形，前肢后指缺失， 主要位于右侧，即后肢右侧前肢拇指错位。 此外，这些药物中的许多都是有充分证据的人类致畸物质，如 如丙戊酸、维甲酸和乙醇。这个假定的原因/结果 适应性反应和局限性肢体畸形之间的关系是 对探索非常有吸引力，因为我们知道一种发育信号 在没有后趾的情况下，肢体发育过程中发生变化的机制。 极化活性，后肢芽中胚层诱导 当移植到宿主雏鸟翅膀的前缘时，肢体重复 被广泛接受为前/后(A/P)模式的基础 在包括人类在内的许多物种中都有肢体。我们已经证明，这项活动 是从乙酰唑胺暴露的四肢中消失的。在具体目标1中，我们将 检验镉暴露类似地减少极化的假设 小鼠肢芽的活性，并将检测其对基因的影响 肢体的表达模式。在具体目标2中，我们建议澄清 肢芽细胞暴露后的适应性反应途径 乙酰唑胺或镉，两者均可引起后肢右前肢 外露的手指。我们将利用微阵列分析来检测应力 对致畸物质暴露的反应。我们假设一个共同的适应性 对乙酰唑胺和镉的反应将被诱导。未来的研究将 检查这种适应性反应的干扰能力 偏振活动，从而导致先天畸形。一个非常好的 令人兴奋的额外好处将是发现和识别新的 在肢体形态发生和/或异种生物反应中很重要的基因。

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.