KINASES/EARLY RESPONSE GENES IN OROFACIAL DEVELOPMENT

各种体液因子，神经递质，生长因子， 已经提出了洋地黄素和离子调节生长， 哺乳动物胚胎腭的分化。 一些影响 发育中的腭中的这些刺激由腺苷-3 '，5'- 一磷酸（cAMP）及其相关激酶，cAMP依赖性蛋白 激酶（cAMP-dPK）。 然而，正常腭发育的复杂性， 依赖于无数的形态学和生物化学过程， 清楚地表明不存在单一的关键调节分子或途径。 毫无疑问，组织形态、细胞形态和细胞形态的广泛改变， 生物化学和细胞增殖，最终导致 哺乳动物中面是多种激素相互作用的结果， 生长因子激活的信号通路。 虽然很多注意力 一直致力于识别生物相关的外部 刺激和影响正常腭发育的细胞受体， 较少注意集中在识别和相互作用， 介导这些效应的多种信号转导途径 外部刺激。 此外，迄今为止，没有任何研究涉及 负责转导短期细胞外的核事件， 跨膜和细胞质信号转化为长期细胞表型 与正常口面发育有关的改变。 因此 本申请提出研究主信号的作用 转导蛋白激酶C（PKC）在介导各种 腭激素和生长因子，以及检查的作用， 蛋白质中的“早期反应”核癌基因家族（fos，myc，jun） 正常生长过程中激酶介导的信号转导， 哺乳动物次生腭的分化。 本申请的总体目标包括：1）确定 PKC同工酶及其mRNA表达时空分布 在发展味觉和定义功能的作用， 胚胎腭突细胞生长信号转导系统 糖胺聚糖合成; 2）时空确定 Fos的“早期反应”核癌基因的表达模式， 由腭激素和生长因子诱导的myc和jun家族， 描绘这些基因在胚胎腭细胞中的功能作用 增殖和代谢; 3）确定是否诱导 发育中的腭中的“早期反应”癌基因是通过以下途径介导的 PKC，并分析cAMP-dPK和PKC之间的潜在“串扰” 信号转导途径;和4）检测乙醇的作用， 一种影响各种口面缺陷的致畸剂， “早期反应”癌基因及其信号转导 发育中的腭。

A variety of humoral agents, neurotransmitters, growth factors, prostaglandins and ions have been suggested to modulate growth and differentiation of the embryonic mammalian palate. The effects of some of these stimuli in the developing palate are mediated by adenosine-3',5'- monophosphate (cAMP) and its associated kinase, cAMP-dependent protein kinase (cAMP-dPK). The complexity of normal palatogenesis, however, which is dependent upon a myriad of morphological and biochemical processes, clearly dictates that no single key regulatory molecule or pathway exists. Undoubtedly, the extensive alterations in tissue morphology, cellular biochemistry, and cell proliferation that culminate in genesis of the mammalian midface result from the interaction of multiple hormone- and growth factor-activated signalling pathways. Although much attention has been directed towards identifying the biologically relevant external stimuli and the cellular receptors affecting normal palate development, less attention has been focused on the identification and interaction of the multiple signal transduction pathways mediating the effects of these external stimuli. Moreover, no studies, to date, have addressed the nuclear events responsible for transducing the short-term extracellular, transmembrane and cytoplasmic signals into long-term cellular phenotypic alterations associated with normal orofacial development. Accordingly, the current application proposes to investigate the role of the major signal transducer protein kinase C (PKC) in mediating the effects of various palatal hormones and growth factors, as well as examine the role of the 'early response' nuclear oncogene families (fos, myc, jun) in protein kinase-mediated signal transduction during normal growth and differentiation of the mammalian secondary palate. The overall objectives of this application include: 1) determination of the spatio-temporal profile of expression of PKC isozymes and their mRNAs in the developing palate and definition of a functional role for this signal transduction system in embryonic palatal cell growth and glycosaminoglycan synthesis; 2) determination of the spatio-temporal pattern of expression of the 'early response' nuclear oncogenes of the fos, myc and jun families induced by palatal hormones and growth factors, and delineation of a functional role for these genes in embryonic palatal cell proliferation and metabolism; 3) determination of whether the induction of the 'early response' oncogenes in the developing palate is mediated through PKC, and analysis of potential "cross-talk" between the cAMP-dPK and PKC signal transduction pathways; and 4) examination of the effects of ethanol, a teratogen affecting varied orofacial defects, on the expression of the "early response" oncogenes and their respective signal transduction pathways in the developing palate.