Identifying the underlying mechanisms of medium chain fatty acids in health using a simple model system

中链甘油三酯（MCT）生酮饮食提供了一系列的健康益处，包括改善行为和认知功能(1)，是一种治疗耐药癫痫的方法，可能还可以治疗脑癌和阿尔茨海默病（2,3）。该饮食包括补充摄入两种主要的中链脂肪，癸酸和辛酸，并被认为通过生成酮起作用（4,5）。然而，我们最近证明了它在癫痫治疗中通过癸酸对神经递质受体的直接作用而起作用。与健康有关的其他行动机制仍有待确定。确定这些机制将大大提高我们对饮食健康益处的理解，这是BBSRC研究的一个优先领域。我们的研究提供了世界领先的例子，使用简单的真核生物盘基ostelium作为一系列生物医学相关研究的创新动物替代模型(6)。我们的突破包括：a)确定丙戊酸在Dictyostelium中治疗癫痫的分子机制（7,8），并将其转化为体外和体内动物模型(9)，从而鉴定出在多种动物模型中有效的新型有效化合物（10,11），并获得两项专利（WO_2012069790_A1, GB_Application_1416017.0），以及发现癸酸在癫痫控制中的靶点（12）。与这一发现相关的临床试验将于2016年初开始。b)确定与药物开发和治疗活性相关的苦味剂靶点（13,14）。c)说明两种与健康/疾病相关的人类蛋白质的同源物的保守作用（13,15）。这些动物替代研究表明，盘基ostelium可以让我们了解与人类健康相关的食物的细胞功能，这是BBSRC资助的另一个优先领域。该项目将包括筛选盘基ostelum突变文库，以确定控制这些食物相关脂肪影响的蛋白质。将研究脂肪依赖性细胞功能的变化，以确定这些食物的分子机制。鉴定的蛋白质的人类同源物将在盘基骨柱中进行分析，哺乳动物细胞系将用于提供转化研究并导致对人类样本的分析。该项目将提供多学科技术方面的高级培训，包括细胞和发育生物学、生物化学、药理学和药物遗传学，以及3r研究及其广泛应用方面的优秀培训。学生还将接受传统（哺乳动物）细胞模型的培训，除了科学写作和在国际会议（年度国际Dictyostelium会议）上的口头报告外，还将为3Rs研究提供一种新的综合方法。

The medium chain tryglyceride (MCT) ketogenic diet provides a range of health benefits including improved behaviour and cognitive function (1), and is a treatment for drug resistant epilepsy, and possibly brain cancer and Alzheimer's disease treatment (2,3). The diet involves the supplementary intake of two main medium chain fats, decanoic and octanoic acid and was thought to act through the generation of ketones (4,5). However, we have recently demonstrated that it acts in epilepsy treatment through a direct effect of decanoic acid on a neurotransmitter receptor. The other mechanisms of actions relating to health remain to be defined. Identifying these mechanisms will significantly improve our understanding of the health benefits of the diet that is a priority area for BBSRC research.Our studies provide world-leading examples of using the simple eukaryote, Dictyostelium, as an innovative animal-replacement model in a range of biomedical-related studies (6). Examples of our breakthroughs include: a) Identifying the molecular mechanism of the epilepsy treatment valproic acid in Dictyostelium (7,8) and the translation of this to in vitro and in vivo animal models (9), leading to the identification novel potent compounds with efficacy in multiple animal models (10,11), with two resulting patents (WO_2012069790_A1, GB_Application_1416017.0) and the discovery of the target of decanoic acid in epilepsy control (12). Clinical trials relating to this discovery are due to start in early 2016. b) Identifying targets for bitter tastants related to drug development and therapeutic activity (13,14). c) Illustrating the conserved roles of homologues of two health/disease related human proteins (13,15).These animal-replacement studies suggest that Dictyostelium can inform our understanding of cellular functions of food relevant to human health, and this is another priority area for BBSRC funding.The project will involve screening a Dictyostelium mutant library to identify proteins controlling the effect of these food related fats. Fat-dependent changes in cell function will be investigated to identify molecular mechanism of these foods. Human homologues of the identified proteins will be analyse in Dictyostelium, and mammalian cell lines will be used to provide translational research and lead to the analysis of human samples.The project will provide advanced training in a multidisciplinary range of techniques, including cell and developmental biology, biochemistry, pharmacology, and pharmacogenetics and outstanding training in 3Rs research and its broad application. The student will also be trained in traditional (mammalian) cell models, providing a new integrated way of working in 3Rs research, in addition to scientific writing and oral presentation at international meetings (the annual International Dictyostelium meeting).