SIGNAL TRANSDUCTION: REGULATION OF MAMMALIAN DEVELOPMENT

在每一个物种的研究有重大的发展转变， 受精和原肠胚形成广泛地改变了 卵子或胚胎有证据表明，这些发展转变 受信号转导事件的影响或调节。 哺乳动物 胚胎发生也不例外， 但是哺乳动物的胚胎例外， 它们表现出独特的发育转变， 致密化、胚泡形成和原始上皮形成 蛋筒研究的最终目的是确定 细胞内信号转导事件及其机制 行动，在重大的发展转型，以了解如何 卵子和胚胎被塑造成新的形状。这些知识将 提供评估发育失败或异常的方法， 以及提供纠正这种缺陷的可能方法 缺陷这些研究以前是不可能的，因为工具和 实验方法直到最近才变得可用，特别是 膜渗透性激酶激动剂和拮抗剂的开发， 钙螯合剂，以及激酶报告染料，纯化制剂 各种激酶及其催化亚单位，以及 各种细胞内信号转导剂。具体目标 建议研究两种发育迁移、受精 (an所有物种共同的事件）和胚胎压实（一个独特的事件 哺乳动物胚胎发生）。拟议的关于 受精时细胞内信号传导是独特的， 以检查细胞内游离钙升高之后的事件。 为了所有的Deve！opmental转换，事件被检查在一个 这是一个机械的层次，而不是一个描述的层次。使用这些工具， 既可以映射信号传导剂的细胞内活性， 并操纵细胞中信号传导剂的激活或抑制， 整个胚胎或胚胎的特定区域，然后进行评估 对胚胎发育的影响。

In every species examined there are major developmental transitions such as fertilization and gastrulation which extensively alter the structure of the egg or embryo. Evidence suggests that these developmental transitions are influenced or regulated by signal transduction events. Mammalian embryogenesis is no exception to this general scenario of regulation through signal transduction, but mammalian embryos are exceptional in that they exhibit unique developmental transitions, specifically embryonic compaction, blastocyst formation, and formation of primitive epithelia in the egg cylinder. The ultimate goal of the research is to identify the intracellular signal transduction events, and their mechanism(s) of action, at the major developmental transitions in order to understand how the egg and embryo are sculpted into a new form. This knowledge will provide a method of assessing developmental failure, or abnormality, such as birth defects as well as provide possible methods of correcting such defects. These studies were not previously possible because the tools and experimental approaches only recently have become available, specifically the development of membrane permeant kinase agonists and antagonists and calcium chelators, as well as kinase reporter dyes, purified preparations of various kinases and their catalytic sub units, and antibodies to various intracellular signal transduction agents. The SPECIFIC AIMS propose investigation of two developmental trafIlsitions, fertilization (an event common to all species) and embryonic compaction (an event unique to mammalian embryogenisis). The proposed studies on the role of intracellular signalling at fertilization are unique in that they propose to examine events subsequent to the rise in intracellular free calcium. For all of the deve!opmental transitions, events are examined at a mechanistic level rather than a descriptive level. Using these tools it is possible to both map the intracellular activity of the signaling agents and to manipulate activation or repression of the signalling agents in the entire embryo or in specific regions of the embryo followed by assessement of their effects on embryogenesis.