KINASES/EARLY RESPONSE GENES IN OROFACIAL DEVELOPMENT

各种体液因子，神经递质，生长因子， 前列腺素和离子被认为可以调节生长和 哺乳动物胚胎味觉的分化。其中一些因素的影响 发育中的腭部的这些刺激是由腺苷-3‘，5’- 一磷酸(CAMP)及其相关的激酶、cAMP依赖蛋白 激酶(cAMP-DPK)。然而，正常上颌骨形成的复杂性， 依赖于无数的形态和生化过程， 清楚地表明，不存在单一的关键调控分子或途径。 毫无疑问，组织形态的广泛变化，细胞 生物化学和细胞增殖，最终导致了 哺乳动物中脸是多种激素和激素相互作用的结果 生长因子激活的信号通路。尽管有很多人关注 一直致力于识别与生物相关的外部 刺激和细胞感受器影响着正常的上颚发育， 较少的注意力集中在识别和相互作用 介导这些效应的多条信号转导通路 外部刺激。此外，到目前为止，还没有研究解决 负责传递短期细胞外信号的核事件， 跨膜和细胞质信号转化为长期的细胞表型 与正常的口腔面部发育相关的改变。因此， 目前的应用建议研究主要信号的作用 转导蛋白激酶C(PKC)在不同组织中的作用 腭部激素和生长因子，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) 正常生长和发育过程中的信号转导 哺乳动物次级上颚的分化。 本申请的总体目标包括：1)确定 PKC同工酶及其mRNAs表达的时空分布 在味觉发育中的作用和它的功能角色的定义 信号转导系统在胚胎腭部细胞生长和发育中的作用 糖胺多糖的合成；2)时空分布的测定 Fos‘早期反应’核癌基因的表达模式， 腭部激素和生长因子诱导的MYC和Jun家族，以及 这些基因在胚胎腭部细胞中的功能定位 增殖和新陈代谢；3)测定是否诱导 发育中的腭部的“早期反应”癌基因是通过 PKC，并分析了Camp-DPK和PKC之间潜在的“串话” 信号转导途径；以及4)检测乙醇的影响， 一种影响各种口腔面部缺陷的致畸剂，对其表达的影响 “早期反应”癌基因及其各自的信号转导 味觉发育过程中的路径。

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.