SIGNAL TRANSDUCTION: REGULATION OF MAMMALIAN DEVELOPMENT

在所研究的每个物种中，都有重大的发育转变，如 作为受精和原肠作用，它广泛地改变了 卵子或胚胎。有证据表明，这些发育转变 受信号转导事件的影响或调节。哺乳动物 胚胎发育也不例外，这是一种普遍的调控情景 通过信号转导，但哺乳动物胚胎在这方面是例外的 它们表现出独特的发育转变，特别是胚胎 原始上皮细胞的致密化、囊胚形成和形成 蛋筒。这项研究的最终目标是确定 细胞内信号转导事件及其机制(S) 行动，在主要的发展过渡时期，以便了解如何 鸡蛋和胚胎被雕刻成一种新的形式。这一知识将会 提供一种评估发育障碍或异常的方法，如 作为出生缺陷，并提供了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出现，具体地说 膜转运蛋白激动剂和拮抗剂的研究进展 钙络合剂，以及激酶报告染料，纯化制剂 不同的激酶及其催化亚单位，以及针对 各种细胞内信号转导因子。具体目标 建议研究两个发育转变：受精 (所有物种共有的事件)和胚胎紧凑(独特的事件 到哺乳动物胚胎发育)。建议进行的研究包括： 受精时的细胞内信号是独特的，因为他们提出 观察细胞内游离钙升高后发生的事件。 对于所有的开发！操作转换，事件都在一个 机械层面，而不是描述性层面。使用这些工具可以 有可能同时映射信号介质的细胞内活性 并操纵激活或抑制中的信令代理 整个胚胎或胚胎的特定区域，然后进行评估 它们对胚胎发育的影响。

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.