Systematic study of cellular cholesterol homeostasis

细胞胆固醇稳态的系统研究

• 批准号: RGPIN-2019-04494
• 负责人: Widenmaier, Scott
• 金额: $ 2.7万
• 依托单位: University of Saskatchewan
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=687025
• 关键词: Systematic; study; cellular; cholesterol; homeostasis

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.**

胆固醇是一种营养物质，在哺乳动物的细胞膜生理中起着核心作用。由于其独特的生物物理特性，胆固醇可以迅速插入膜中，建立功能屏障，这对于确保细胞参与维持生命的生物活动的稳态环境至关重要。重要的是，胆固醇产生这些影响的水平在不同类型的膜（即细胞膜）之间显著不同。质膜与内质网膜)，即使这些膜特异性水平的微小偏差也会引起细胞应激和损伤，并可能导致病理和致命的后果。换句话说，哺乳动物的生存依赖于动物体内细胞膜的能力能够避免胆固醇过少或过多，而每种膜都有不同的阈值。这种具有挑战性的代谢约束表明，协调胆固醇稳态以确保膜稳态的机制是一种基本进化关系的基础。******虽然胆固醇在膜上的重要作用是众所周知的，但将胆固醇丰度和不均匀分布与膜稳态联系起来的细胞机制却知之甚少。我对nserc资助的研究项目的长期愿景是定义这些机制背后的分子参与者和作用模式，并利用这些见解来确定其进化起源，并预测这一过程如何受到环境压力（如营养挑战、污染和气候变化）的影响。在这个项目的初始阶段，我的团队将开始系统地识别调节内质网膜胆固醇水平的蛋白质，并确定这些蛋白质确保细胞稳态的机制基础。关注内质网的原因是众所周知，它是协调细胞胆固醇稳态的关键部位，也是维持胆固醇浓度阈值的独特挑战的细胞器。因此，我预测内质网配备了限制胆固醇稳态水平的专门防御机制。上述研究将在细胞培养模型系统上进行，该系统先前显示出胆固醇代谢研究的几个优势，并将采用先进的分子技术、系统生物学和生物化学。总的来说，这个项目为学生和研究员提供了尖端的技术培训，以及丰富的智力环境，使发现显著提高我们对胆固醇稳态和膜生物学的基本理解。鉴于胆固醇在哺乳动物中广泛而基本的作用，这些见解可能会对生物科学的广泛学科产生重大影响