Mechanisms of Lipid Droplet Protein Targeting

脂滴蛋白靶向机制

• 批准号: 9145416
• 负责人: Tobias C Walther
• 金额: $ 35.62万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 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 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9145416
• 关键词: Address; Atherosclerosis; Binding; Binding Proteins; Biochemistry; Biological Models; Biology; Biophysics; Cell physiology; Cellular biology; Chlamydia; Coat Protein Complex I; Computational Technique; Coronary heart disease; Crowding; Cytoplasm; Cytosol; Disease; Drosophila genus; Emulsions; Enzymes; Familial generalized lipodystrophy; Fatty Liver; Goals; Grant; Growth; Health; Hepatitis C; Homeostasis; Human; Hydrophobicity; Hyperlipidemia; Infection; Integral Membrane Protein; Intervention; Lecithin; Life; Lipids; Lipodystrophy; Liver diseases; Mammalian Cell; Mediating; Membrane; Membrane Lipids; Membrane Proteins; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Modeling; Molecular; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organelles; Pathology; Phase; Phospholipids; Phosphorylcholine; Physics; Play; Proteins; Proteome; Proteomics; Research; Risk; Role; Specificity; Surface; Testing; Therapeutic; Triglycerides; Variant; Virus Diseases; Work; aqueous; cancer cachexia; combat; innovation; lipid I; lipid metabolism; membrane synthesis; monolayer; non-alcoholic fatty liver; obesity treatment; pathogen; protein E; therapeutic development; trafficking; treatment site

Project Summary Cellular metabolic energy is stored in the form of neutral lipids, particularly triacylglycerols (TGs), which are packaged in cytoplasmic lipid droplets (LDs). Excessive accumulation of LDs occurs during the progression of many diseases, including obesity, type 2 diabetes, atherosclerosis and metabolic syndrome. In addition, LDs play a key role in some infections, including hepatitis C virus and chlamydia, by facilitating replication of some pathogens. Despite their important role in human health and disease, surprisingly little is known about LDs. LDs consist of a hydrophobic core surrounded by a phospholipid monolayer. Most functions of LDs, including TG synthesis, TG storage, and energy mobilization, are executed and regulated by these surface proteins. How these proteins are specifically targeted to LDs, however, remains unclear. Among organelles, LDs are unique because their surface is at the interface of a hydrophobic phase (the LD core) and an aqueous phase (the cytoplasm) and thus are unable to accommodate typical transmembrane proteins with globular domains. Therefore, the targeting of proteins to LDs must involve unique mechanisms. In this project, we will determine how proteins are specifically targeted to the surface of LDs. We will investigate how triglyceride enzymes including GPAT4 and others re-localize to LDs, enabling their growth. In addition, we will determine how amphipathic helix-containing proteins, including the rate-limiting phosphatidylcholine enzyme CTP:phosphocholine cytidylyltransferase (CCT), are specifically targeted to the surface of LDs from the cytosol to facilitate expansion. For each part of the project, we will use cutting-edge biophysics, biochemistry, cell biology, proteomics and computational techniques and validate our findings in different model systems such as Drosophila and mammalian cells. Although the research proposed here is basic, the determination of the fundamental cellular mechanisms that drives lipid droplet protein targeting will nevertheless facilitate the development of therapeutic strategies to combat obesity, metabolic diseases and viral infections, as well as propel further research into the cell biology of these organelles.

项目概要 细胞代谢能量以中性脂质的形式储存，特别是三酰甘油（TG）， 包装在细胞质脂滴（LD）中。 LD 的过度积累发生在疾病进展过程中。 许多疾病，包括肥胖、2型糖尿病、动脉粥样硬化和代谢综合征。此外，LD 通过促进某些病毒的复制，在某些感染（包括丙型肝炎病毒和衣原体）中发挥关键作用 病原体。 尽管 LD 在人类健康和疾病中发挥着重要作用，但令人惊讶的是人们对 LD 知之甚少。 LD 包括 被磷脂单层包围的疏水核。 LD 的大部分功能，包括 TG 合成、 TG 储存和能量动员由这些表面蛋白执行和调节。这些如何 然而，蛋白质是否专门针对 LD 仍不清楚。在细胞器中，LD是独一无二的 因为它们的表面位于疏水相（LD 核心）和水相（LD 核心）的界面处 细胞质），因此无法容纳具有球状结构域的典型跨膜蛋白。 因此，蛋白质靶向 LD 必须涉及独特的机制。 在这个项目中，我们将确定蛋白质如何特异性地靶向 LD 表面。我们将 研究甘油三酯酶（包括 GPAT4 和其他酶）如何重新定位到 LD，从而促进其生长。在 此外，我们将确定含两亲性螺旋的蛋白质（包括限速蛋白）如何 磷脂酰胆碱酶 CTP：磷酸胆碱胞苷酰转移酶 (CCT)，专门针对 LD 表面脱离细胞质以促进扩增。对于项目的每个部分，我们都将使用最先进的技术 生物物理学、生物化学、细胞生物学、蛋白质组学和计算技术，并验证我们的发现 不同的模型系统，例如果蝇和哺乳动物细胞。虽然这里提出的研究是 基本的，驱动脂滴蛋白靶向的基本细胞机制的确定将 尽管如此，仍有助于制定治疗策略来对抗肥胖、代谢疾病和 病毒感染，并推动对这些细胞器的细胞生物学的进一步研究。