TRANSGENIC MODELS OF RETINOID TOXICOLOGY & TERATOGENESIS

描述：维甲酸（RA）是生物活性的衍生物， 维生素A和维生素A缺乏导致涉及组织的病理学 退化 RA治疗逆转了许多病理过程。 胚胎在原肠胚形成时暴露于高水平的RA是致畸的。 此外，许多基因家族被RA激活，包括 Hox基因家族 该项目旨在进一步描述 类维生素A和RA诱导的毒理学和致畸作用的分子生物学， 使用转基因小鼠模型。 这项建议涉及使用各种转基因小鼠模型来检查 毒性剂量维甲酸对Hoxa-1和Hoxa-2基因调控的影响 在胎儿发育的关键阶段表达。 正确的 这些含同源框基因表达的时空模式是 对颅面和其他头部的正常发育至关重要 地区 由于同样的区域受到致畸剂量的 由于新发现的视黄酸反应元件 在Hox基因组的3'端发现了一个RARE基因， 视黄酸可能通过引导 这些基因的异位表达 首席研究员打算 首先确定这些基因的假定调控区域，然后， 定点突变，以测试结合位点的功能， 转基因小鼠中的调节因子。 下一个阶段涉及以下方面的作用： Hoxa-1和Hoxa-2基因敲除在发育过程中表达的RARE 模型 最后，他们打算检查Hoxa-1对表型的贡献， 通过给予Hoxa-1基因敲除小鼠毒性剂量的RA观察到类维生素A毒性。 作为最后一个目标的一部分，他们还想看看Hox的变化 在视黄酸受体（RAR）敲除小鼠中的表达。

DESCRIPTION: Retinoic acid (RA) is the biologically active derivative of vitamin A and deficiencies of vitamin A lead to pathologies involving tissue degeneration. RA treatment reverses many of the pathological processes. Embryonic exposure to high levels of RA at gastrulation is teratogenic. Furthermore, a number of gene families are activated by RA, including the Hox gene family. This project endeavors to further characterize the molecular biology of retinoid- and RA-induced toxicology and teratogenesis, using transgenic mouse models. This proposal involves using various transgenic mouse models to examine the effects of toxic doses of RA on the regulation of Hoxa-1 and Hoxa-2 gene expression during critical stages of fetal development. The correct spatiotemporal patterns of expression of these homeobox-containing genes are critical for the normal development of the craniofacial and other head regions. Since the same regions are affected by teratogenic doses of retinoic acid, and since a newly discovered retinoic acid response element (RARE) has been found at the 3' end of the Hox gene group, there is a strong possibility that retinoic acid exerts its toxic effects through directing the ectopic expression of these genes. The principal investigator intends to first identify putative regulatory regions of these genes and then, by site directed mutagenesis, to test the functions of binding sites of regulatory factors in transgenic mice. The next phase involves the role of the RARE in Hoxa-1 and Hoxa-2 expression in development using a knockout model. Lastly, they intend to examine Hoxa-1 contribution to the phenotype seen in retinoid toxicity by giving Hoxa-1 knockout mice toxic doses of RA. As part of this last goal, they also want to look at changes in Hox expression in retinoic acid receptor (RAR) knockout mice.