Lipidic drivers of organelle function and dysregulation

项目总结 脂质代表了一种不同类别的生物分子，它们是细胞膜的组成部分。近年来， 脂类成分的改变已被确认为多种疾病的特征，从2型到 糖尿病到神经退行性疾病。然而，了解散装膜脂的功能作用 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。我们的实验室 应用遗传和化学手段研究脂质功能并开发膜生物物理模型-- 相关的细胞过程。拟议的研究计划将实施这一方法，以确定两个 与疾病相关的脂质紊乱改变了细胞隔间的行为。在第一个推力中，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控制 呼吸代谢。具体地说，我们将在这两个酵母中设计内部线粒体膜成分 和哺乳动物细胞系，并利用这种微扰来剖析扩散和超分子 组装到电子传输链上。这一努力将揭示哺乳动物保守特征的功能 线粒体，如呼吸超复合体，并测试由以下因素引起的饱和脂肪增加 代谢紊乱可能直接导致线粒体功能障碍。在第二个推力中，我们将使用 询问1-脱氧鞘磷脂功能的遗传系统，丝氨酸的非规范产物- 棕榈酰基转移酶与几种遗传和代谢紊乱有关。我们将重点关注 1-脱氧鞘磷脂的合成如何影响视网膜色素上皮的膜系统 这些细胞与1-脱氧核酸脂堆积引起的成年性失明有关。发展 新的成像方法的出现将把这一推力的影响扩大到这些新的生物医学角色 神秘的脂类。如果执行，该研究计划将因此产生两组脂类分子和 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如何改变 在跨细胞器、细胞和组织的脂质组成中产生和发挥作用，并利用这一知识来揭示 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.