Lipidic drivers of organelle function and dysregulation

细胞器功能和失调的脂质驱动因素

• 批准号: 10456925
• 负责人: Itay Budin
• 金额: $ 39.5万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10456925
• 关键词: Adult; Blindness; Cell Line; Cell membrane; Cell physiology; Cells; Chemicals; Development; Diffusion; Disease; Electron Transport; Engineering; Genetic; Genetic Diseases; Goals; Health; Human; Image; Inner mitochondrial membrane; Knowledge; Laboratories; Link; Lipids; Mammalian Cell; Mechanics; Membrane; Membrane Biology; Membrane Lipids; Metabolic Diseases; Metabolism; Mitochondria; Modeling; Molecular; Neurodegenerative Disorders; Non-Insulin-Dependent Diabetes Mellitus; Organelles; Phospholipids; Research; Respiration; Role; Sphingolipids; Structure; Structure of retinal pigment epithelium; System; Testing; Tissues; Unsaturated Fats; Viscosity; Yeasts; biophysical model; biophysical techniques; cell behavior; genetic approach; imaging approach; membrane model; mitochondrial dysfunction; programs; respiratory; saturated fat; serine palmitoyltransferase; tool; Adult; Blindness; Cell Line; Cell membrane; Cell physiology; Cells; Chemicals; Development; Diffusion; Disease; Electron Transport; Engineering; Genetic; Genetic Diseases; Goals; Health; Human; Image; Inner mitochondrial membrane; Knowledge; Laboratories; Link; Lipids; Mammalian Cell; Mechanics; Membrane; Membrane Biology; Membrane Lipids; Metabolic Diseases; Metabolism; Mitochondria; Modeling; Molecular; Neurodegenerative Disorders; Non-Insulin-Dependent Diabetes Mellitus; Organelles; Phospholipids; Research; Respiration; Role; Sphingolipids; Structure; Structure of retinal pigment epithelium; System; Testing; Tissues; Unsaturated Fats; Viscosity; Yeasts; biophysical model; biophysical techniques; cell behavior; genetic approach; imaging approach; membrane model; mitochondrial dysfunction; programs; respiratory; saturated fat; serine palmitoyltransferase; tool

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.

项目摘要 脂质代表了各种各样的生物分子，这些生物分子是细胞膜的基础。最近几年， 脂质成分的改变已被确定为多种疾病的标志，从2型 神经退行性疾病的糖尿病。但是，了解散装膜脂质的功能作用 长期以来，一直是一个挑战，部分原因是操纵和成像细胞的困难。我们的实验室 应用遗传和化学工具来研究脂质功能并开发膜的生物物理模型 相关的细胞过程。拟议的研究计划将执行这种方法，以确定两个 与疾病相关的脂质扰动改变了细胞室的行为。在第一个推力中，我们将使用 饱和磷脂对膜粘度的影响，以发现结构和动力学如何控制 呼吸新陈代谢。具体而言，我们将在两种酵母中设计内部线粒体膜组成 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 组装到电子传输链。这项工作将揭示哺乳动物保守特征的功能 线粒体，例如呼吸系统超复合物，并测试如何导致饱和脂质的增加 代谢性疾病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 遗传系统以询问1-脱氧脂肪的功能，这是丝氨酸的非人类产物 与几种遗传和代谢性疾病有关的棕榈酰转移酶。我们将重点关注 1-脱氧脂肪的合成如何使视网膜色素上皮中的内膜系统失调 细胞与1-脱氧脂肪累积引起的成人发病相关。发展 新的成像方法将扩大这种推力对新兴生物医学作用的影响 神秘的脂质。如果执行，研究程序将为两组脂质分子和 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 在细胞器，细胞和组织跨脂质组成中，出现和功能，并利用这些知识来发现 膜生物学基础的分子机制。