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Cytoskeletal Regulation Of Vesicle Transport In Liver

肝脏囊泡运输的细胞骨架调节

基本信息

批准号：
9903273
负责人：
MARK A. MC NIVEN
金额：
$ 35.78万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
1992
资助国家：
美国
起止时间：
1992-02-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9903273
关键词：
Architecture Autophagocytosis Award Binding Biological Biological Assay Catabolism Cell physiology Cells Complex Critical Pathways Diabetes Mellitus Docking Dynamin Dynamin 2 Electron Microscopy Energy-Generating Resources Enzymes Event Extended Family Failure Family Family member Fatty Liver Fatty acid glycerol esters Goals Grant Guanosine Health Hepatic Hepatocyte In Vitro Incidence Inflammation Lead Link Lipids Liver Liver diseases Lysosomes Mediating Membrane Metabolic Diseases Mitochondria Molecular Non-Insulin-Dependent Diabetes Mellitus Normal Cell Optic Atrophy Organelles Pathway interactions Physiology Play Prevention Process Production Protein Binding Domain Proteins Regulation Resolution Role Seminal Site Structure Synapses Testing Therapeutic Intervention Transmembrane Transport Triglycerides Work apical membrane in vivo innovation insight lipid metabolism liver inflammation new therapeutic target non-alcoholic fatty liver disease novel novel strategies oxidation protein complex receptor trafficking vesicle transport

项目摘要

PROJECT SUMMARY/ABSTRACT This proposal represents the renewal of a grant that was converted to an R37 MERIT award in 2007. Its long- term objective has been centered on identifying key cytoskeletal components that orchestrate membrane and receptor trafficking pathways critical to liver physiology. Recently, we have expanded our efforts to additionally examine the contributions of autophagy, due to its direct relevance in hepatic function and the important fact that this process shares significant mechanistic overlap with the secretory and endocytic pathways. Non- alcoholic fatty liver disease (NAFLD), with underlying hepatic steatosis and inflammation, is rapidly becoming a prominent health issue. This proposal is focused on the fundamental mechanisms that regulate the autophagic hepatocellular breakdown and utilization of unique triglyceride-rich organelles, lipid droplets (LDs), for use as an energy source by mitochondria. Significant evidence implicates the selective targeting and breakdown of hepatic LDs by the autophagic machinery in a process called lipophagy. We, and others, have demonstrated that important components of this essential cellular process are large and small guanosine triphosphatases (GTPases). These include the Ras-like Rab GTPases that control many membrane-trafficking processes in the hepatocyte and the Dynamin (Dyn) family of large GTPase mechanoenzymes that mediate membrane scission/fusion throughout the cell. We have made seminal contributions toward the identification and functional analysis of these enzymes in the hepatocyte. We have recently found that they play an important role in hepatic lipophagy; specifically, that a subset of Rab GTPases mediate the interaction, docking, and envelopment of LD in the hepatocyte by nascent autophagic membranes. We have also observed that a subset of these Rabs appear to bind Dyn proteins at the LD and mitochondria to regulate lipid metabolism. These findings support this proposal's central hypothesis that large and small GTPases work synergistically to mediate lipophagy and catabolism in the hepatocyte by regulating the interactions between LDs, autophagic membranes, and mitochondria. The following specific aims represent novel and innovative biological concepts in this proposal: 1) determining how a specific sub-family of Rab GTPases (Rabs 8, 10, and 13) interact with the large GTPase Dyn2 to coordinate the establishment and extension of the phagophore during hepatic lipophagy; 2) defining the mechanism by which the autophagic phagophore extends around the LD during lipophagy in the hepatocyte through the action of a novel membrane-deforming Rab effector protein complex (EHD2 and EHBP1); and 3) defining the role of mitochondrial-associated Dyns in the structural relationship between the LD, autolysosome, and mitochondria during hepatic energy production. Completion of these studies will provide valuable insights into hepatocellular lipid metabolism, resulting in a better understanding of the underlying basis for hepatic steatosis, leading to novel strategies for therapeutic intervention in NAFLD.

项目摘要/摘要这项提议代表着一项赠款的续期，该赠款于2007年转换为R37卢比功绩奖。它很长- 术语目标一直集中在确定协调细胞膜和细胞骨架的关键成分受体转运途径对肝脏生理至关重要。最近，我们已将我们的努力扩大到另外检查自噬的贡献，因为它与肝功能直接相关，而且重要的事实这一过程与分泌和内吞途径有显著的机械重叠。非- 酒精性脂肪性肝病(NAFLD)，伴随着肝脏脂肪变性和炎症，正迅速成为一种突出的健康问题。这项提案的重点是监管自噬的基本机制。肝细胞的分解和独特的富含甘油三酯的细胞器--脂滴(LDS)的利用线粒体提供的能量来源。有重要证据表明，有选择性的目标和崩溃在一种称为脂噬的过程中，自噬机制导致肝脏LDS。我们和其他人已经证明这个重要的细胞过程的重要组成部分是大的和小的鸟苷三磷酸酶 (GTP酶)。这些包括RAS样Rab GTP酶，它控制着许多膜转运过程肝细胞与大分子GTP酶机械酶家族中的动力蛋白(Dyn) 整个细胞的分裂/融合。我们为鉴定和鉴定做出了重大贡献这些酶在肝细胞中的功能分析。我们最近发现，他们扮演着一个重要的角色在肝脏脂噬中的作用；具体地说，Rab GTP酶的一个子集介导相互作用、对接和新生自噬膜包被肝细胞中的LD。我们还观察到，这些RAB的亚群似乎与LD和线粒体上的Dyn蛋白结合，以调节脂质代谢。这些发现支持了这一提议的中心假设，即大小GTP酶协同作用通过调节低密度脂蛋白、自噬蛋白和低密度脂蛋白之间的相互作用来调节肝细胞的脂噬和分解代谢膜和线粒体。以下具体目标代表了新颖和创新的生物学概念在这项建议中：1)确定特定的Rab GTP酶亚家族(RAB 8、10和13)如何与大的GTP酶DYN2在肝脏中协调吞噬细胞的建立和扩展脂噬作用；2)确定自噬噬菌体在LD周围扩展的机制一种新的膜变形性Rab效应蛋白复合体在肝细胞中的吞脂作用 (EHD2和EHBP1)；以及3)确定线粒体相关DyN在结构关系中的作用肝脏能量产生过程中LD、自溶酶体和线粒体之间的相互作用。完成这些工作研究将对肝细胞脂质代谢提供有价值的见解，从而更好地了解肝脏脂肪变性的潜在基础，导致治疗非酒精性脂肪肝的新策略。