Systematic study of cellular cholesterol homeostasis

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Cholesterol is a nutrient that plays a central role in the physiology of cell membranes in mammals. Due to its unique biophysical properties cholesterol can rapidly intercalate into membranes to establish a functional barrier, which is essential to secure the homeostatic environment within which cells engage in the biological activities that sustain life. Importantly, the level at which cholesterol renders these effects significantly varies between differing types of membranes (ie. plasma membrane versus endoplasmic reticulum membrane), and even small deviations in these membrane specific levels causes cell stress and damage and can lead to pathological and lethal consequences. In other words, the survival of mammalian animals is dependent on the ability of cell membranes within that animal being able to avoid having too little and having too much cholesterol, and with each type of membrane having a different threshold. Such a challenging metabolic constraint suggests the mechanisms that coordinate cholesterol homeostasis to secure membrane homeostasis underlies a fundamental evolutionary relationship. Though the vital role of cholesterol on membranes is well known, the cellular mechanisms linking cholesterol abundance and non-uniform distribution to membrane homeostasis is poorly understand. My long term vision for an NSERC-funded research program is to define the molecular players and mode of action underlying these mechanisms, and use such insights to identify its evolutionary origin and predict how this process might be impacted by environmental pressures such as nutrient challenges, pollution, and changes in climate. During this initial phase of the program, my group will begin systematically identifying the proteins that regulate cholesterol levels in the endoplasmic reticulum membrane and determine the mechanistic basis by which these proteins secure cellular homeostasis. The reason for focusing on endoplasmic reticulum is that it is well known as a crucial site for coordinating cellular cholesterol homeostasis and as an organelle with unique challenges in maintaining concentration thresholds of cholesterol. Therefore, I predict the endoplasmic reticulum is equipped with specialized defense mechanisms that constrain homeostatic levels of cholesterol. The aforementioned studies will be undertaken on a cell culture model system previously shown to exhibit several advantages for the study of cholesterol metabolism, and will employ advanced molecular techniques, systems biology, and biochemistry. Altogether, this program offers cutting-edge technical training for students and fellows, as well as an enriching intellectual environment for making discoveries that significantly improve our basic understanding of cholesterol homeostasis and membrane biology. Given the broad and fundamental roles of cholesterol in mammals, such insights are likely to have a significant impact across a broad range of disciplines in the biological sciences.