MOLECULAR MECHANISM AND DEVELOPMENT CONSEQUENCES OF ICSI

辅助生殖技术(ART)的实践 在过去的两年中，人类不孕不育症急剧增加。 几十年来，细胞质内精子的广泛使用达到了顶峰 注射(ICSI)，可以克服以前的不孕症 被认为是难以处理的。由于进行的固有的困难 有限人力物力和政府力量的基础研究 禁止对人类卵子和植入前胚胎进行基础研究， 艺术的发展本质上是在缺乏基础的情况下发生的。 使用动物模型系统进行研究。从本质上讲，这是一个例子 艺术先于科学。在这项拨款申请中，我们建议使用鼠标 作为一个模型系统来研究分子机制和 ICSI的发育/行为后果。卵子的能力是 HCG后孤雌生殖刺激激活的时间随时间延长而增加 管理并与中期II进展相关--停滞 卵子进入类似间期的状态。第一个具体目标将考验 假设，类似于孤雌生殖卵子激活，成功 人绒毛膜促性腺激素诱导的卵泡刺激率随时间延长而增加 行政管理。虽然ICSI显然已经彻底改变了对 男性不育，ICSI如何激活卵子的分子基础 启动早期开发计划的人知之甚少， 尤其是考虑到ICSI绕过了使用的正常途径 通过精子使卵子受精。了解病毒的分子基础 卵胞浆内单精子注射激活卵子将不可避免地产生对原因的理解 对于它的失败和提高其效力的基本方法。这个 第二个特定目标将检验ICSI招募信号的假设 在自然的过程中通常被激活的通路 受精和卵子事件的正常补充 激活。ICSI作为一种可选择的方法迅速得到使用 克服人类男性不育引发了一场关于 对由此产生的后代施加的长期风险。尽管它是 乍一看令人放心的是，没有明显的显著增长 ICSI来源的粗大先天性异常的发生率 后代，这些孩子还很小，因此影响更微妙 对行为和智力发展的影响可能还没有 很明显。第三个特定目标将检验小鼠ICSI的假设 导致轻微的发育和行为异常 所产生的后代。

The practice of Assisted Reproductive Technology (ART) to overcome infertility in humans has increased dramatically during the past two decades and has culminated in the widespread use of intracytoplasmic sperm injection (ICSI), which can overcome instances of infertility previously thought to be intractable. Due to the inherent difficulty of conducting basic research with the limited amounts of human material and governmental bans on basic research of human eggs and pre-implantation embryos, the development of ART hs occurred essentially in the absence of basic research using an animal model system. In essence, this is an example of ART before science. In this grant application, we propose to use the mouse as a model system to study the molecular mechanism and developmental/behavioral consequences of ICSI. The ability of eggs to be activated by parthenogenetic stimuli increases with the time post-hCG administration and correlates with progression of metaphase II-arrested eggs into an interphase-like state. The first Specific Aim will test the hypothesis that, similar to parthenogenetic egg activation, the success of ICSI-induced egg activation increases with time following hCG administration. While ICSI has clearly revolutionized the treatment of male infertility, the molecular basis of how ICSI activates the egg and initiates the program of early development is poorly understood, especially in light of the fact that ICSI bypasses the normal pathway used by the sperm to fertilize the egg. Understanding the molecular basis of egg activation by ICSI will inevitably yield an understanding as to causes for its failure and rationale approaches to enhances its efficacy. The second Specific Aim will test the hypothesis that ICSI recruits signaling pathways that are normally activated during the course of natural fertilization and results in the normal complement of events of egg activation. The rapidly gaining use of ICSI as the method-of-choice to overcome human male infertility has raised a vigorous debate concerning the long-term risk imposed to the resultant offspring. Although it is reassuring at first glance that there is no apparent significant increase in the incidence of gross congenital abnormalities in ICSI-derived offspring, these children are still young and hence more subtle effects that influence behavioral and intellectual development may not yet be apparent. The third Specific Aim will test the hypothesis that mouse ICSI results in subtle developmental and behavior abnormalities in the generated offspring.