Hypoxic Injury and Tumor Formation in the C. elegans Germline

项目总结/摘要 氧气对人体生理的各个方面都至关重要。因此，缺氧可显著损害 或改变细胞功能，这可能对人类健康和生存能力产生破坏性后果。 阻塞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，并构成西方国家死亡和残疾的主要原因。 国家在其他生理背景下，缺氧可以刺激癌症的生长和转移，另一个是缺氧。 人类的重大疾病。由于这些原因，人们对开发 减轻缺氧病理后果的策略。线虫C. elegans已经证明 是研究缺氧损伤机制和确定潜在策略的有力模型 进行干预。利用C.线虫能够进行诱变和RNAi筛选， 共鉴定了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 揭示了尽管缺氧的主要影响是氧化磷酸化的简单失败， 缺氧的最终影响由多种代谢和细胞功能决定。通过 发现了许多与缺氧损伤有关的新机制。elegans提供了一个重要的 对外地的贡献。我们认为C。elegans提出了最有利的模型， 研究这些机制。梭秀丽线虫的生殖系具有多种细胞类型， 生理环境，因此我们推断，这可能是一个特别有用的背景下， 了解缺氧可能影响细胞功能的新方式。我们的初步研究表明 证实了这一点，并建立了潜在的种系调查缺氧的三个重要方面， 损伤我们的第一个目标是确定一般和细胞特异性缺氧损伤的机制。第二 目的是表征诱导对缺氧损伤的抗性的新机制。我们的第三个目标是 了解缺氧如何导致肿瘤在C.秀丽隐杆线虫生殖系强大的实验工具 生殖系的有趣的生理特性为实现我们的每一个目标提供了独特的优势。 目标.我们希望这些研究具有相当大的生物医学意义，因为我们将建立 一般和细胞特异性干预的潜力，确定缺氧诱导机制的潜力 抗性，并阐明缺氧诱导的癌症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.