Lipidic drivers of organelle function and dysregulation

项目摘要 脂质代表了作为细胞膜的构建块的不同类别的生物分子。近年来， 脂质组成的改变已被确定为许多疾病的标志， 糖尿病到神经退行性疾病然而，了解大量膜脂质的功能作用， 长期以来一直是一个挑战，部分原因是在细胞中操纵和成像它们的困难。本实验室 应用遗传和化学工具研究脂质功能，并开发膜的生物物理模型， 相关的细胞过程。拟议的研究计划将采用这种方法来确定两个 疾病相关的脂质扰动改变细胞区室的行为。在第一次进攻中，我们将使用 饱和磷脂对膜粘度的影响，以揭示结构和动力学如何控制 呼吸代谢具体来说，我们将在两种酵母中设计线粒体内膜成分， 和哺乳动物细胞系，并使用这种扰动来剖析扩散和超分子的贡献， 组装到电子传递链上。这项工作将揭示哺乳动物细胞中保守特征的功能， 线粒体，如呼吸超复合物，并测试如何增加饱和脂质引起的 代谢紊乱可直接导致线粒体功能障碍。在第二个推力中，我们将使用 遗传系统来询问1-脱氧鞘脂的功能，丝氨酸的非典型产物， 棕榈酰转移酶与几种遗传和代谢疾病有关。我们将专注于 1-脱氧鞘脂的合成如何失调视网膜色素上皮细胞内膜系统 细胞，这与1-脱氧鞘脂积累引起的成人失明有关。发展 新的成像方法将扩大这一推力的影响，以新兴的生物医学作用， 神秘的脂质如果执行，该研究计划将产生两组脂质分子的模型， 它们在健康和患病细胞中的细胞作用点。我们的长期目标是了解 在细胞器、细胞和组织脂质组成中产生和发挥作用，并利用这些知识来揭示 膜生物学的分子机制。

PROJECT SUMMARY Lipids represent a diverse class of biomolecules that are the building blocks of cell membranes. In recent years, alterations in lipid composition have been identified as hallmarks of numerous diseases, ranging from type 2 diabetes to neurodegenerative disorders. However, understanding the functional roles of bulk membrane lipids has long been a challenge, in part due to the difficulties of manipulating and imaging them in cells. Our laboratory applies genetic and chemical tools to study lipid function and develop biophysical models for membrane- associated cellular processes. The proposed research program will carry out this approach to identify how two disease-associated lipid perturbations alter the behavior of cellular compartments. In the first thrust, we will use effects of saturated phospholipids on membrane viscosity to uncover how structure and dynamics control respiratory metabolism. Specifically, we will engineer inner mitochondrial membrane composition in both yeast and mammalian cell lines and use this perturbation to dissect the contributions of diffusion and supramolecular assembly to the electron transport chain. This effort will uncover the function of conserved features of mammalian mitochondria, such as respiratory supercomplexes, and test how increases in saturated lipids caused by metabolic disorders could directly contribute to mitochondrial dysfunction. In the second thrust, we will use a genetic system to interrogate the function of 1-deoxysphinglipids, non-canonical products of serine- palmitoyltransferase that have been associated with several genetic and metabolic disorders. We will focus on how synthesis of 1-deoxysphinglipids dysregulates the endomembrane system in retinal pigment epithelium cells, which have been linked to adult-onset blindness caused by 1-deoxysphinglipid accumulation. Development of new imaging approaches will broaden the impact of this thrust to the emerging biomedical roles for these enigmatic lipids. If executed, the research program will thus generate models for two sets of lipids molecules and their cellular points of action in both healthy and diseased cells. Our long-term goal is to understand how changes in lipid composition across organelles, cells, and tissues arise and function, and use this knowledge to uncover the molecular mechanisms underlying membrane biology.