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

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).