SIGNAL TRANSDUCTION: REGULATION OF MAMMALIAN DEVELOPMENT

在每个被检查的物种中都存在重大的发育转变，例如 受精和原肠胚形成极大地改变了结构 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 胚胎发生对于这种一般的调控情况也不例外 通过信号转导，但哺乳动物胚胎的特殊之处在于 它们表现出独特的发育转变，特别是胚胎时期 压实、囊胚形成和原始上皮细胞的形成 蛋缸。研究的最终目标是确定 细胞内信号转导事件及其机制 行动，在主要的发展转变，以了解如何 卵子和胚胎被雕刻成新的形态。这些知识将 提供一种评估发育失败或异常的方法，例如 以及提供纠正这种出生缺陷的可能方法 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 透膜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抗体 各种细胞内信号转导剂。具体目标 提出对两种发育转变、受精的研究 （所有物种共有的事件）和胚胎压缩（独特的事件） 哺乳动物胚胎发生）。拟议的作用研究 受精时的细胞内信号传导是独特的，因为他们提出 检查细胞内游离钙增加后的事件。 对于所有的发展转变，都会在一定程度上检查事件 机械层面而非描述层面。使用这些工具是 可以绘制信号剂的细胞内活性图 并操纵信号转导剂的激活或抑制 整个胚胎或胚胎的特定区域，然后进行评估 其对胚胎发生的影响。

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.