MOLECULAR ANALYSIS OF ETHANOL-INDUCED OROFACIAL DEFECTS

大量的临床和实验证据表明，酒精 孕期饮酒会导致各种不良妊娠 结果。宫内酒精引起的多系统异常 暴露，称为“胎儿酒精综合症”(FAS)，包括：1)前和 出生后发育迟缓，2)头面部缺陷，如 小头畸形、眼睑短裂隙、面中部发育不全和唇裂 唇腭裂和3)中枢神经系统功能障碍 包括不典型的新生儿行为，智力障碍，以及 发育迟缓。尽管相关的临床和实验研究 对Fas的反应一直很强烈，酒精致畸的机制 仍然是个谜。鉴于在以下方面取得了重大进展 探讨酒精性中枢神经系统的发病机制 异常情况下，几乎没有提供关于 颌面部显著畸形的细胞机制(S) 与Fas有关，尽管面部特征 表型是酒精致畸的最具代表性的特征。 现有临床和实验文献处理的优势 与酒精诱发的口面部畸形是一种描述性的性质 这表明乙醇的细胞和分子机制 干扰正常的口面部个体发育还不够充分 地址。Fas的主要表型表现，尤其是在 口面部发育不全。因此，在当前 应用，我们建议分析几个基本的细胞和分子 过程，其扰动可能导致面部发育不全 表型，如Fas儿童的特征。自正常以来 面部的生长和个体发育在很大程度上取决于 精确编排的细胞增殖模式和速度，以及 细胞外基质大分子表达谱，以及自 在几个成人和胎儿中，这两个都是酒精的作用部位 组织，有理由推测这些过程可能是 发育中口腔面部乙醇的细胞靶点。 由于乙醇对细胞事件的直接影响的研究 颌面的个体发育是机械学进步的关键 假设，我们的总体目标将集中在当前的应用中 1)乙醇对细胞增殖影响的测定 在发育中的小鼠口面部突起和关于2)分析 乙醇对多种细胞外基质表达的影响 小鼠口腔面部个体发育过程中的大分子。

Substantial clinical and experimental evidence indicates that alcohol consumption during pregnancy results in a variety of adverse pregnancy outcomes. The multisystem abnormalities resulting from in utero alcohol exposure, termed "fetal alcohol syndrome" (FAS), include: 1) pre- and postnatal growth retardation, 2) cranial/facial defects such as microcephaly, short palpebral fissures, midfacial hypoplasia, and cleft lip and/or cleft palate and 3) central nervous system dysfunction including atypical neonatal behavior, intellectual impairment, and developmental delays. Although clinical and experimental research related to FAS has been intense, the mechanisms underlying alcohol teratogenicity remain an enigma. Whereas significant strides have been made in addressing the pathogenesis of alcohol-induced central nervous system abnormalities, few, if any, insights have been provided regarding the cellular mechanism(s) underlying the striking orofacial dysmorphology associated with FAS, despite the fact that a characteristic orofacial phenotype is the most indicative feature of alcohol teratogenesis. The preponderance of existing clinical and experimental literature dealing with alcohol-induced orofacial dysmorphology is a descriptive nature indicating that the cellular and molecular mechanisms whereby ethanol interferes with normal orofacial ontogenesis have yet to be adequately addressed. The principal phenotypic manifestation of FAS, particularly in the orofacial region, is hypoplasia. Therefore, in the current application, we propose to analyze several basic cellular and molecular processes, perturbation of which could result in a hypoplastic facial phenotype such as that characteristic of children with FAS. Since normal growth and ontogenesis of the facial region is largely dependent on precisely orchestrated patterns and rates of cell proliferation, and expression of repertoire of extracellular matrix macromolecules, and since both of these are sites of action for alcohol in several adult and fetal tissues, it is reasonable to speculate that these processes may be cellular targets of ethanol in the developing orofacial region. Since studies on the direct effects of ethanol on cellular events during orofacial ontogenesis are critical to the advancement of mechanistic hypotheses, our overall objectives in the current application will focus on: 1) determination of the effects of ethanol on cellular proliferation in the developing murine orofacial processes and on 2) analysis of the effects of ethanol on the expression of various extracellular matrix macromolecules during murine orofacial ontogenesis.