Genetic pathway and cellular mechanism underlying organismic responses to hypoxia and hypothermia

项目摘要/摘要 适当的温度和氧气水平使基本的生命活动成为可能。低温(低温)和 氧气水平的降低(缺氧)普遍影响基本的生化过程，细胞 新陈代谢、生物体生理和行为。低氧和氧化应激也是 缺血性疾病，包括中风和心脏病发作，其治疗可以从新出现的 “治疗性亚低温”的程序。我们的实验室对基础基因分析和 有弹性的生物体中缺氧、低温、先天缺血耐受的机制研究 新陈代谢应激引起的组织损伤的细胞保护。我们使用的是基因上易驯服的线虫 从细胞生理和组织行为异常的大规模筛选中分离到的突变体 低氧/低体温反应的表型和2)已知的唯一自交的红树林金枪鱼 基因与线虫相似的脊椎动物，已知的与线虫相关的极端生理表型 低氧和低体温，作为发现工具。此外，我们在体外培养哺乳动物神经干细胞。 从冬眠地松鼠中分离出来以解开缺氧/低温的细胞内在机制 宽容。通过多学科的方法和技术，我们一直在进行富有成效的研究 程序，并已经发现了基因、蛋白质变体和途径的新作用机制 赋予细胞保护和机体对低氧和低温的反应。在此R35应用程序中，我们 建议继续这些易于处理和创新的调查路线，以扩大我们对如何 细胞和生物体应对低氧和低温，以表征已经存在的新基因和途径 从我们的正向遗传和RNAi筛查中识别，并识别先天的关键遗传决定因素 恢复力生物体的缺氧/缺血耐受性。PI和实验室丰富的先前经验和 在不同但互补的模型系统方面的专业知识非常适合执行并成功 在加州大学旧金山分校心血管研究所完成该项目 (加州大学旧金山分校)因为Mira R35的目的是“支持整合NIGMS对多个项目的支持，这些项目可能 与我们的情况一样，我们将平衡用于每个模型系统的努力和资源， 对于解决我们研究计划中的相同核心问题，这些问题同样容易处理。

Project Summary/Abstract Proper temperature and oxygen levels enable essential life activities. Low temperature (hypothermia) and reduced level of oxygen (hypoxia) pervasively influence fundamental biochemical processes, cellular metabolism, organismic physiology and behaviors. Hypoxia and oxidative stresses are also key features in ischemic disorders, including stroke and heart attack, treatment of which can greatly benefit from the emerging procedure of “therapeutic hypothermia.” Our laboratory is interested in fundamental genetic analysis and mechanistic studies of hypoxia, hypothermia, innate ischemic tolerance in resilient organisms, and cytoprotection against tissue injuries caused by metabolic stresses. We use 1) genetically tractable C. elegans mutants isolated from large-scale screens with abnormal cell physiological and organismic behavioral phenotypes in hypoxia/hypothermia responses and 2) Mangrove Killifish, the only known self-fertilizing vertebrate with genetics similar to that of C. elegans and known extreme physiological phenotypes related to hypoxia and hypothermia, as discovery tools. In addition, we culture mammalian neural stem cells ex vivo isolated from hibernating ground squirrels to unravel cellular intrinsic mechanisms of hypoxia/hypothermia tolerance. With multidisciplinary approaches and technologies, we have been running a productive research program and already discovered novel mechanisms of action of genes, protein variants and pathways in conferring cytoprotection and organismic responses to hypoxia and hypothermia. In this R35 application, we propose to continue these tractable and innovative lines of inquiries to expand our basic understanding of how cells and organisms cope with hypoxia and hypothermia, to characterize novel genes and pathways already identified from our forward genetic and RNAi screens, and to identify key genetic determinants of innate hypoxia/ischemic tolerance in resilient organisms. The PI and laboratory's extensive prior experience and expertise in diverse but complementary model systems are well suited for executing and successfully completing the project in the Cardiovascular Research Institute at the University of California, San Francisco (UCSF). As the MIRA R35 is intended to “enable consolidation of NIGMS support for multiple projects that may be disparate” as is our case, we will balance efforts and resources dedicated to each of the model systems, which are similarly tractable towards addressing the same core questions in our research program.