Mechanisms of Lipid Droplet Protein Targeting

脂滴蛋白靶向机制

• 批准号: 10524777
• 负责人: Tobias C Walther
• 金额: $ 37.6万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10524777
• 关键词: Address; Adopted; Atherosclerosis; Binding; Biochemical; Buffers; Cells; Cellular biology; Cytoplasm; Defect; Development; Disease; Drosophila genus; Enzymes; Funding; Generations; Human; Hydrolysis; Industry; Intervention; Lead; Link; Lipids; Lipodystrophy; Lipolysis; Liver diseases; Mediating; Membrane; Metabolic; Metabolic Diseases; Metabolism; Modeling; Molecular; Molecular Conformation; Monomeric GTP-Binding Proteins; Obesity; Oils; Organelles; Organism; Pathology; Pathway interactions; Phase; Phosphatidylinositols; Phospholipids; Physiology; Plants; Process; Proteins; Proteome; Reticulum; SNAP receptor; Surface; Testing; Therapeutic; Triglycerides; Variant; cell type; driving force; fatty liver disease; genome wide screen; genome-wide; high risk; insight; lipid metabolism; membrane biogenesis; monolayer; non-alcoholic fatty liver disease; novel therapeutics; sterol ester

PROJECT SUMMARY Lipid storage is a fundamental process for organisms to buffer fluctuations in the availability and need for metabolic energy. Lipids are predominantly stored as neutral lipids, such as triacylglycerols (TGs), in organelles called lipid droplets (LDs). These organelles are hubs of metabolism with most of their biochemical functions being executed by proteins targeting their surface. Consistent with the important function of LD proteins in metabolism, their aberrant accumulation on LDs can cause diseases, such as liver disease or lipodystrophy. Despite the fundamental importance of LD proteins and their intimate link to human physiology and pathology, little is known about the mechanisms how protein target LDs. In this proposal, we address this question for some of the most important lipid metabolism enzymes that target LDs after initial insertion into the endoplasmatic reticulum. Capitalizing on results from the previous funding period, we will define the machinery building bridges between the ER and LDs for protein targeting and decipher the molecular driving forces for transport to LDs. Completing these aims will reveal a fundamental aspect of evolutionarily conserved cell biology. Since accumulation of protein variants on LDs causes common metabolic diseases, our may also provide new therapeutic avenues for intervention.

项目总结 脂质储存是生物体缓冲可获得性和需要的波动的基本过程 新陈代谢能量。脂质主要以中性脂的形式储存在细胞器中，如三酰甘油(Tgs)。 称为脂滴(LDS)。这些细胞器是新陈代谢的枢纽，具有大部分的生化功能。 被以其表面为靶标的蛋白质执行。与LD蛋白在体内的重要功能一致 在新陈代谢过程中，它们在低密度脂蛋白上的异常堆积会导致疾病，如肝脏疾病或脂肪营养不良。 尽管LD蛋白的基本重要性及其与人类生理和病理的密切联系， 人们对蛋白质靶向LDS的机制知之甚少。在这项提案中，我们为一些人解决了这个问题 在最初插入内质后，以LDS为靶点的最重要的脂代谢酶 网状结构。我们将根据前一个资助期的结果，确定建造桥梁的机械 在内质网和LDS之间进行蛋白质靶向，并破译运输到LDS的分子驱动力。 完成这些目标将揭示进化保守的细胞生物学的一个基本方面。自.以来 LDS上蛋白质变异的积累导致常见的代谢性疾病，我们的研究也可能提供新的 干预的治疗途径。