Genetics/Cell Biology of Anoxia in C.elegans

描述（由申请人提供）：极度缺氧是涉及心脏和肺功能障碍的几种疾病的病理学核心。氧剥夺也在实体肿瘤对放射或化学治疗的抵抗中起作用。了解遗传和细胞反应的缺氧抗性生物体缺氧，缺氧将促进治疗的发展，用于挽救受损的缺血组织，或缺氧的肿瘤细胞的破坏。我们发现线虫C.线虫能够在长时间暴露于缺氧（<0.001kPa氧气）下存活。暴露于缺氧的胚胎导致细胞周期和发育进程的完全停滞。一旦再次暴露于氧气，这些过程就会恢复。本研究的长期目标是表征线虫对缺氧的分子和细胞反应。该申请的中心假设是胚胎包含一个遗传程序，以协调生物过程的停滞，例如响应缺氧的细胞分裂。以前，我们发现纺锤体检查点是胚胎在缺氧条件下将卵裂球阻滞在中期所必需的。我们将使用遗传和细胞生物学技术的组合，以进一步研究之间的途径缺氧和细胞分裂停滞在线虫胚胎追求以下目标。目标1。检查纺锤体检查点组件在暴露于缺氧的胚胎中的反应。以前我们发现纺锤体检查点成分（san-1和mdf-2）是胚胎缺氧存活所必需的。我们将使用遗传和细胞生物学技术来扩展这一发现。 目标二。使用RNA干扰来识别胚胎发育不需要的基因，但胚胎在缺氧中存活所需的基因。细胞生物学技术将用于确定这些基因产物是否是卵裂球在缺氧时阻止细胞周期所必需的。

DESCRIPTION (provided by applicant): Extreme oxygen deprivation is central to the pathology of several diseases involving cardiac and pulmonary dysfunction. Oxygen deprivation also plays a role in the resistance of solid tumors to radiation or chemotherapy treatment. Understanding the genetic and cellular response oxygen-deprivation resistant organisms have to anoxia, hypoxia will facilitate the development of treatment for the rescue of damaged ischemic tissue, or the destruction of oxygen deprived tumor cells. We found that the nematode C. elegans is capable of surviving prolonged exposure to anoxia (<.001 kPa Oxygen). Embryos exposed to anoxia leads to a complete arrest of cell cycle and developmental progression. Upon reexposure to oxygen, these processes are resumed. The long-term goal of this research is to characterize the molecular and cellular responses nematodes have to oxygen deprivation. The central hypothesis of this application is that embryos contain a genetic program to coordinate the arrest of biological processes such as cell division in response to anoxia. Previously, we found that the spindle checkpoint is required for embryos to arrest blastomeres in metaphase during exposure to anoxia. We will use a combination of genetic and cell biological techniques to further investigate the pathway between oxygen deprivation and cell division arrest in the nematode embryo by pursuing the following aims. Aim 1. Examine the response the spindle checkpoint components have in embryos exposed to anoxia. Previously we found that the spindle checkpoint components (san-1 and mdf-2) are required for embryos to survive anoxia. We will use genetic and cell biological techniques to expand on this finding. Aim 2. Use RNA interference to identify genes that are not required for embryo development, but are required for embryos to survive anoxia. Cell biological techniques will be used to determine if these gene products are required for blastomeres to arrest the cell cycle in response to anoxia.