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

项目概要/摘要 适当的温度和氧气水平使基本的生命活动。低温（hypothermia） 氧气水平降低（缺氧）普遍影响基本的生化过程，细胞 代谢、器官生理和行为。缺氧和氧化应激也是脑缺血的关键特征。 缺血性疾病，包括中风和心脏病发作，其治疗可以大大受益于新兴的 “治疗性低温”。我们的实验室对基础遗传分析感兴趣， 对适应性生物体中缺氧、低温、先天缺血耐受的机制研究，以及 对代谢应激引起的组织损伤的细胞保护。我们使用1）遗传上易处理的C。elegans 从大规模筛选中分离出的具有异常细胞生理和器官行为的突变体 表型在缺氧/低温反应和2）红树林刀鱼，唯一已知的自我繁殖 遗传学上与C相似的脊椎动物。和已知的极端生理表型有关 缺氧和体温过低作为探索工具此外，我们体外培养哺乳动物神经干细胞， 从冬眠的地松鼠中分离出来，以揭示缺氧/体温过低的细胞内在机制 宽容通过多学科方法和技术，我们一直在进行富有成效的研究， 程序和已经发现的新机制的作用基因，蛋白质变体和途径， 赋予细胞保护和器官对缺氧和低温的反应。在R35应用中，我们 我建议继续这些易于处理和创新的调查路线，以扩大我们的基本理解，如何 细胞和生物体科普缺氧和体温过低，以表征新的基因和途径已经 从我们的正向遗传和RNAi筛选中鉴定出，并鉴定先天性 缺氧/缺血耐受性恢复有机体。PI和实验室的丰富经验， 在不同但互补的模型系统方面的专业知识非常适合执行和成功 在弗朗西斯科加州大学心血管研究所完成了这个项目 （UCSF）。由于MIRA R35的目的是“使NIGMS支持多个项目， ”就像我们的情况一样，我们将平衡致力于每个模型系统的努力和资源， 这是同样易于处理的解决同样的核心问题，在我们的研究计划。

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.