Hypoxic Injury and Tumor Formation in the C. elegans Germline

项目摘要/摘要 氧气对人体生理的各个方面都是至关重要的。因此，缺乏氧气可能会严重损害 或改变细胞功能，这可能会对人类健康和生存能力造成毁灭性的后果。 阻止血液循环和阻止氧气输送的生理事件，如心脏病发作或中风， 对受影响的组织造成致命损害，并构成西部地区死亡和残疾的主要原因 国家。在其他生理环境中，缺氧可以刺激癌症的生长和转移，另一种 人类疾病具有相当重要的意义。出于这些原因，人们对开发 减轻缺氧的病理后果的策略。线虫秀丽线虫已经证明 是研究低氧损伤机制和确定潜在策略的有力模型 进行干预。利用线虫的遗传优势启用诱变和RNAi筛选 总共确定了200多个与缺氧损伤有关的基因。这一发现很有启发性，因为它 研究表明，虽然缺氧的主要影响是简单的氧化磷酸化失败， 缺氧的最终后果是由多种代谢和细胞功能决定的。通过 发现过多与线虫缺氧损伤有关的新机制提供了一个重要的 对这一领域的贡献。我们相信线虫代表了未来最有利的模式 对这些机制的调查。线虫生殖系拥有多种细胞类型和 生理环境，因此我们推断这可能是一个特别有用的环境 了解低氧可能影响细胞功能的新方式。我们的初步研究已经 证实了这一点，并建立了生殖系研究低氧的三个重要方面的潜力 受伤。我们的第一个目标是确定缺氧性损伤的一般和细胞特异性机制。第二 目的是研究一种诱导耐缺氧损伤的新机制。我们的第三个目标是 了解缺氧是如何导致线虫种系中的肿瘤形成的。强大的实验工具 而生殖系有趣的生理特性为实现我们的每一个 目标。我们预计这些研究将具有相当大的生物医学意义，因为我们将建立 一般干预和细胞特异性干预的可能性，确定低氧诱导机制的可能性 并阐明了低氧诱导肿瘤形成的基本保守机制。

Project Summary/Abstract Oxygen is critical for all aspects of human physiology. Accordingly, oxygen deprivation can significantly impair or alter cellular functions, which can have devastating consequences to human health and viability. Physiological events that block circulation and prevent the delivery of oxygen, such as heart attack or stroke, cause lethal damage to affected tissues and comprise the leading cause of death and disability in Western countries. In other physiological contexts, hypoxia can stimulate the growth and metastasis of cancer, another human disease of considerable significance. For these reasons, there is substantial interest in developing strategies for alleviating the pathological consequences of hypoxia. The nematode C. elegans has proven to be a powerful model for investigating the mechanisms of hypoxic injury and for identifying potential strategies for intervention. Enlisting the genetic advantages of C. elegans enabled mutagenic and RNAi screens which together identified over 200 genes involved in hypoxic injury. This finding was enlightening because it revealed that although the primary effect of oxygen deprivation is a simple failure of oxidative phosphorylation, the ultimate repercussions of hypoxia are decided by a multitude of metabolic and cellular functions. By discovering a plethora of new mechanisms involved in hypoxic injury C. elegans has provided a significant contribution to the field. We believe C. elegans presents the most advantageous model for further investigation into these mechanisms. The C. elegans germline harbors a diverse array of cell types and physiological environments, therefore we reasoned that it might be a particularly useful context for understanding novel ways in which hypoxia may impact cellular function. Our preliminary studies have confirmed this, and established the potential of the germline to investigate three important aspects of hypoxic injury. Our first aim is designed to identify general and cell-specific mechanisms of hypoxic injury. The second aim is to characterize a novel mechanism for inducing resistance to hypoxic injury. And our third aim is to understand how hypoxia causes tumors to form in the C. elegans germline. The powerful experimental tools and interesting physiological properties of the germline offer unique advantages for achieving each of our objectives. We expect these studies to be of considerable biomedical significance, as we will establish the potential of general and cell-specific interventions, determine the potential for inducible mechanisms of hypoxia resistance, and elucidate fundamental conserved mechanisms of hypoxia induced cancer formation.