Systems Biology of the hypoxic adaptation

真核生物的一个关键但鲜为人知的方面是感知和适应当地环境中氧气浓度的变化的能力。缺氧是一种氧气供应减少的状态，许多生物体在各种生理和疾病条件下都会经历这种状态。低氧导致细胞新陈代谢的实质性重塑以及能量产生的减少，因此，生物体必须发展复杂的机制来应对氧气消耗。我们项目的目的是了解氧气耗竭是如何感觉到的，并确定对适应这种环境至关重要的生物过程。我们选择在白色念珠菌中研究这些方面，这是一种单细胞真核生物，具有常氧和低氧双重生活方式。白念珠菌是一种共生酵母菌，既存在于人体需氧部位，包括皮肤和粘膜表面，也存在于缺氧部位，如内脏。因此，白色念珠菌是研究新陈代谢和生长适应对氧气波动的反应的一个有吸引力的模型。*我们将进行系统的遗传筛选，以确定感知和适应氧气耗竭所需的基因。将对候选基因进行功能表征，并将使用不同的遗传和基因组方法剖析它们在介导低氧适应中的作用。我们的初步研究支持这样一个模型，即通过测量线粒体产生的细胞能量(ATP)的下降来感知缺氧。这一假说将通过使用遗传、化学基因组学和细胞生物学工具的不同互补方法进行验证。*缺氧是一种生物状态，与不同的临床问题有关，与许多健康疾病有关，如缺血性心脏病、脑缺血、癌症和产科/围产期并发症等。缺氧也是食品业的关键因素，主要影响发酵生物过程和水产养殖。因此，该项目将产生有关缺氧生物学的基本知识，这些知识可以转化为其他应用领域，包括生物技术和医学。

A critical but poorly understood aspect of an eukaryotic organism is the ability to sense and adapt to variations in the oxygen concentration in the local environment. Hypoxia is a state of a reduced oxygen availability that is experienced by many organisms under numerous physiological and disease conditions. Hypoxia leads to a substantial remodeling of cell metabolism in addition to a reduction of energy production and thus, organisms must develop sophisticated mechanisms to cope with oxygen depletion. The aim of our project is to understand how oxygen depletion is sensed and to identify biological processes that are essential for adaptation in such environment. We opt to study these aspects in Candida albicans, which is a unicellular eukaryotic organism that has a dual normoxic and hypoxic lifestyle. C. albicans is a commensal yeast that inhabits both aerobic human body sites including skin and mucosal surfaces, as well as oxygen-poor locations such as internal organs. Thus, C. albicans is an attractive model to study metabolic and growth adaptations in response to oxygen fluctuations.*We will undertake a systematic genetic screen to identify genes required for the perception and the adaptation to oxygen depletion. The candidate genes will be functionally characterized and their role in mediating hypoxia adaptation will be dissected using different genetic and genomic approaches. Our preliminary investigations are supportive of a model where hypoxia is sensed through gauging the drop of cellular energy (ATP) generated by mitochondria. This hypothesis will be tested by different complementary approaches using genetic, chemogenomic and cellular biology tools. *Hypoxia is a biological state related to different clinical problems associated with many health disorders such as ischemic heart disease, cerebral ischemia, cancers and obstetrical/perinatal complications etc. Hypoxia is also a critical factor in food industry affecting mainly fermentative bioprocess and aquaculture farming. Thus, this project will generate fundamental knowledge on the biology of hypoxia that can be translated to other field of application including biotechnology and medicine.