Sorting and trafficking in the endosomal system

内体系统中的分选和运输

基本信息

批准号：
8577299
负责人：
Christopher G Burd
金额：
$ 36.63万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-09-01 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8577299
关键词：
1-Phosphatidylinositol 3-Kinase Address Affect Alzheimer&apos s Disease Area Biochemical Biogenesis Biological Biological Assay Cardiovascular Diseases Cell membrane Cell physiology Cells Cellular Stress Complement Complex Core Protein Cues Defect Development Disease Dynamin Endosomes Enzymes Family Fluorescence Microscopy Funding Goals Golgi Apparatus Guanosine Triphosphate Phosphohydrolases Homeostasis In Vitro Integral Membrane Protein Laboratories Lead Life Lipids Lysosomal Storage Diseases Lysosomes Malignant Neoplasms Mannose Mass Spectrum Analysis Mediating Membrane Metabolic Methods Molecular Nutrient Nutritional Organelles Pathway interactions Physiological Play Process Protein Family Proteins Proteome Proteomics Reaction Recruitment Activity Recycling Regulation Research Research Project Grants Research Proposals Role SNAP receptor Set protein Signal Transduction Sorting - Cell Movement Surface System Testing Time Transferrin Receptor Tubular formation Vesicle Yeasts base biological adaptation to stress cell growth cellular imaging endosome membrane in vivo inorganic phosphate insight macromolecule member mutant nervous system disorder nexin phosphatidylinositol 3-phosphate protein complex public health relevance receptor reconstitution research study response retrograde transport sorting nexins time use trafficking trans-Golgi Network yeast genetics

项目摘要

DESCRIPTION (provided by applicant): The broad goal of this research project is to elucidate the mechanisms by which proteins and lipids in the endosome are packaged into transport carriers that bud from the endosome and ferry cargo to the Golgi apparatus and other organelles. These trafficking pathways, collectively termed 'endosomal retrograde transport,' are vital for cell physiology and homeostasis, metazoan development and they counter poorly understood processes that contribute to lysosomal storage diseases, cancer, Alzheimer's disease, and other diseases. In previous funding cycles we discovered that retrograde pathways are used to modulate the composition of the plasma membrane in response to environmental and nutritional cues, and we established roles for a soluble protein sorting complex called 'retromer' and three effectors of Phosphatidylinositol 3-kinase (PI3K) called sorting nexin (SNX) proteins. These components assemble on the endosome membrane where they capture and package cargo into budding transport carriers but the underlying mechanisms are unknown. With the principle cellular function of retromer now well established, the major challenge for the field is to elucidate the mechanisms by which it functions. Biochemical approaches will be used to dissect the mechanism of retromer assembly with cargo on the endosome membrane. These experiments will complemented with live cell imaging of retrograde transport that will place the assembly reactions in a physiological context. In recognition that the retromer sorting nexins are members of a much larger SNX protein family for which the functions of all but a few have been described, unbiased, proteome scale experiments will be used to elucidate the functions of each sorting nexin and to assess their specific contributions to cell physiology.

描述（由申请人提供）：该研究项目的总体目标是阐明内体中的蛋白质和脂质被包装成运输载体的机制，该运输载体从内体中出芽并将货物运送到高尔基体和其他细胞器。这些运输途径统称为“内体逆行运输”，对于细胞生理学和体内平衡、后生动物的发育至关重要，并且它们对抗导致溶酶体贮积病、癌症、阿尔茨海默病和其他疾病的人们知之甚少的过程。在之前的资助周期中，我们发现逆行途径用于调节质膜的组成以响应环境和营养线索，并且我们确定了称为“retromer”的可溶性蛋白质分选复合物和磷脂酰肌醇 3-激酶的三个效应子的作用（ PI3K）称为分选连接蛋白（SNX）蛋白。这些组件在内体膜上组装，在那里它们捕获货物并将其包装到萌芽的运输载体中，但潜在的机制尚不清楚。随着逆转录酶的主要细胞功能现已得到很好的确立，该领域面临的主要挑战是阐明其发挥作用的机制。将使用生化方法来剖析内体膜上的逆转录酶与货物的组装机制。这些实验将与逆行运输的活细胞成像相补充，将组装反应置于生理环境中。认识到逆转录酶分选 nexin 是一个更大的 SNX 蛋白家族的成员，其中除了少数几个外，所有蛋白的功能都已被描述，无偏见的蛋白质组规模实验将用于阐明每个分选 nexin 的功能并评估其特异性对细胞生理学的贡献。