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局部环境中氧浓度变化的能力。缺氧是许多生物体在许多生理和疾病条件下所经历的氧气可用性降低的一种状态。缺氧除了导致能量产生的减少外，还会导致细胞代谢的重塑，因此，生物体必须发展出复杂的机制来应对氧气的消耗。我们项目的目的是了解氧气损耗是如何被感知的，并确定在这种环境中适应所必需的生物过程。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，具有双重常氧和缺氧的生活方式。白色念珠菌是一种共生酵母菌，既存在于需氧人体部位，包括皮肤和粘膜表面，也存在于缺氧部位，如内脏。因此，白色念珠菌是研究代谢和生长适应对氧气波动的一个有吸引力的模型。我们将进行系统的基因筛选，以确定感知和适应缺氧所需的基因。候选基因将被功能表征，它们在调节缺氧适应中的作用将使用不同的遗传和基因组方法进行剖析。我们的初步研究支持一个模型，即通过测量线粒体产生的细胞能量（ATP）的下降来感知缺氧。这一假设将通过使用遗传学、化学基因组学和细胞生物学工具的不同互补方法进行测试。缺氧是一种生物学状态，与多种临床问题相关，如缺血性心脏病、脑缺血、癌症和产科/围产期并发症等。在食品工业中，缺氧也是一个关键因素，主要影响发酵生物过程和水产养殖。因此，该项目将产生关于缺氧生物学的基础知识，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.