GROWTH FACTORS/ONCOGENES IN ABNORMAL PALATE DEVELOPMENT

描述（改编自研究者摘要）：腭裂（CP）是一种 常见的人类畸形，其病因和发病机制仍然存在 这在很大程度上是未知的，主要是因为细胞机制介导的正常 腭的发育过程还不完全清楚。 Secalonic acid D（SAD）是越来越多的环境污染物之一。 化学物质和压力能够诱导CP的后代暴露 实验用啮齿动物 同时暴露于二甲基亚砜（DMSO） 几乎完全消除了SAD诱导的CP的发生率。 进一步 有证据表明，SAD和DMSO诱导的致畸性均 保护作用可能涉及SAD诱导的母体糖皮质激素水平升高 用DMSO进行归一化处理。 最近的证据表明 外源性糖皮质激素、SAD、 其它腭裂致畸剂可能涉及正常个体发育的改变 某些生长因子和致癌基因的影响。 这些 已知分子沿着蛋白激酶在细胞凋亡中起关键作用。 参与细胞增殖、分化和 正常胚胎发育以及腭发育中的其他关键事件。 的 研究的主要目的是深入了解 Secalonic acid D（SAD）在小鼠腭裂发病中的作用 是 预期SAD相关的发病机制与唇腭裂有关， 由其他环境因素引起的腭发育。 主要研究者 为实现这一目标，努力实现3个具体目标和7个 假设 第一个目标集中在一个概念，即正常发展的 小鼠次级腭表现出空间和时间模式， 表皮生长因子（EGF）和癌基因（myc和ras）的分布， 并含有显著活性的蛋白激酶（A和C）。 第二 具体目标集中在腭裂致畸剂SAD改变的想法， 腭中一种或多种信号分子的个体发育。 第三个具体目标是解决保护剂DMSO 逆转SAD诱导的蛋白激酶A减少和c-myc增加， 而不是其他参数。 这些研究的结果将使 用于鉴定SAD诱导的这些非常重要的 信号机制，并将重点缩小到最相关的 通过同时识别通过以下方式标准化（逆转）的途径来改变 保护剂DMSO。 此外，这些结果也可能是 与CP的发病机制有关， 化学品、药物和压力似乎也会提高产妇的 糖皮质激素 CP发病机制的鉴定是 在制定预防战略以应对这一常见的人类疾病方面， 畸形

DESCRIPTION (Adapted from investigator's Abstract): Cleft palate (CP) is a common human malformation for which the etiology and pathogenesis remain largely unknown mainly because the cellular mechanisms mediating normal developmental processes in the palate are incompletely understood. Secalonic acid D (SAD) is among an increasing number of environmental chemicals and stresses capable of inducing CP in the offspring of exposed experimental rodents. Simultaneous exposure to dimethyl sulfoxide (DMSO) almost completely abolished the incidence of SAD-induced CP. Further evidence indicates that both the teratogenicity of SAD and DMSO-induced protection may involve SAD-induced increase in maternal glucocorticoid level and it's normalization by DMSO, respectively. Recent evidence indicates that the pathogenesis of CP induced by exogenous glucocorticoids, SAD and other cleft palate teratogens may involve alterations in the normal ontogeny of certain growth factors and oncogenes in the developing palate. These molecules along with protein kinases are known to play critical roles in the signalling pathways involved in cellular proliferation, differentiation, and other key events in normal embryonic, and thus palatal, development. The main objective of the study is to gain insight into the mechanisms of pathogenesis of cleft palate in mice by Secalonic acid D (SAD). It is expected that the SAD-related pathogenesis is relevant to cleft palatogenesis by other environmental causes. The Principal Investigator attempts to achieve this objective by addressing 3 specific aims and 7 hypotheses. The first aim focuses on the notion that the normal developing murine secondary palate exhibits a spatial and temporal pattern of distribution of epidermal growth factor (EGF), and oncogenes (myc and ras), and contains significant activity of protein kinases (A and C). The second specific aim focuses on the idea that the cleft palate teratogen SAD alters the ontogeny of one or more of these signalling molecules in the palate. The third specific aim addresses the idea that the protective agent DMSO reverses SAD-induced decrease in protein kinase A and increase in c-myc but not the other parameters proposed. The results of these studies will allow for identification of SAD-induced alterations in these very important signalling mechanisms, and for narrowing the focus to the most relevant changes by simultaneously identifying pathways(s) normalized (reversed) by the protective agent, DMSO. Further, these results are also likely to be relevant to the pathogenesis of CP by a large number of environmental chemicals, drugs and stresses that also seem to elevate maternal glucocorticoids. Identification of the mechanisms of pathogenesis of CP is critical in devising preventive strategies to deal with this common human malformation.