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Apical protein sorting in renal epithelial cells

肾上皮细胞顶端蛋白质分选

基本信息

批准号：
9102156
负责人：
Ora A Weisz
金额：
$ 33.5万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9102156
关键词：
Acute Kidney Failure Affect Apical Avidity Binding Binding Proteins Biochemical Blood Circulation Carbohydrates Cell Polarity Cell membrane Cell physiology Cell surface Cells Cellular biology Cytoplasmic Protein Cytoplasmic Tail Defect Dimerization Disease Endosomes Epithelial Cells Face Family Galactose Binding Lectin Galectin 4 Goals Health Hypertension Ions Kidney Kidney Diseases Life Link Lipids MDCK cell Maintenance Mammals Mediating Membrane Proteins Modeling Mucin 1 protein Mutation Pathway interactions Play Polysaccharides Proteins Proteomics Recruitment Activity Recycling Renal carcinoma Renal function Research Role Route Signal Transduction Sorting - Cell Movement Staging Surface Testing Therapeutic Universities Urine Water Work Zebrafish apical membrane base basolateral membrane biophysical techniques carbohydrate binding protein combat crosslink design dimer endolyn kidney cell knock-down luminal membrane member monomer mutant nephrogenesis overexpression podocalyxin polypeptide protein protein interaction protein transport sialomucins sialylation trafficking trans-Golgi Network

项目摘要

DESCRIPTION (provided by applicant): Kidney cell function requires the maintenance of polarized plasma membrane domains with distinct protein and lipid compositions, and defects in proper targeting of proteins results in disease. Despite the critical role of cell polarity in maintaining kidney function, we know little about the mechanisms that selectively guide proteins to the apical and basolateral cell surfaces. Our long term goal is to understand how proteins are segregated and targeted to the apical surface of kidney cells with the objective of manipulating protein sorting to treat disease. Apical sorting signals are diverse and multiple biosynthetic routes exist to the apical plasma membrane. Here we propose a unifying model for apical protein sorting in which cargo clustering within sorting compartments provides the avidity necessary to recruit membrane and cytoplasmic proteins required for surface delivery. We will test this model using a protein with an essential role in kidney function that is targeted to the apical surface in a glycan dependent manner. Our proposed studies utilize cutting edge biophysical, biochemical, and proteomic approaches and take full advantage of the unique facilities and broad expertise in renal epithelial cell biology at the University of Pittsburgh. Ths work will significantly enhance our understanding of how apical sorting and polarity are maintained in the kidney and illuminate new strategies to manipulate protein traffic for therapeutic advantage.

描述（由申请人提供）：肾细胞功能需要维持具有不同蛋白质和脂质组成的极化质膜结构域，并且蛋白质正确靶向的缺陷会导致疾病。尽管细胞极性在维持肾功能中发挥着关键作用，但我们对选择性引导蛋白质到达顶端和基底外侧细胞表面的机制知之甚少。我们的长期目标是了解蛋白质如何分离并靶向肾细胞的顶端表面，目的是操纵蛋白质分选来治疗疾病。顶端分选信号多种多样，并且顶端质膜存在多种生物合成途径。在这里，我们提出了一种用于顶端蛋白质分选的统一模型，其中分选室内的货物聚集提供了招募表面递送所需的膜和细胞质蛋白质所需的亲合力。我们将使用一种在肾功能中发挥重要作用的蛋白质来测试该模型，该蛋白质以聚糖依赖性方式靶向顶端表面。我们提出的研究利用了最先进的生物物理、生物化学和蛋白质组学方法，并充分利用匹兹堡大学在肾上皮细胞生物学方面的独特设施和广泛的专业知识。这项工作将显着增强我们对肾脏中如何维持顶端排序和极性的理解，并阐明操纵蛋白质运输以获得治疗优势的新策略。