Regulation of Apical Specific Endocytosis in the C. elegans Intestine

秀丽隐杆线虫肠道顶端特异性内吞作用的调节

• 批准号: 7573401
• 负责人: Barth Demian Grant
• 金额: $ 17.92万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-17 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7573401
• 关键词: Affect; Animal Model; Antibodies; Antigens; Apical; Area; Biological Models; Caenorhabditis elegans; Cell Surface Proteins; Cell Surface Receptors; Cell membrane; Cells; Chloride Channels; Clathrin; Complement; Complex; Coupled; Disease; Dysentery; Endocytosis; Endosomes; Enterocytes; Enterotoxins; Epithelial Cells; Excision; Fluids and Secretions; Foundations; Future; Genes; Genetic; Genetic Models; Glucose Transporter; Goals; Homeostasis; Imagery; Integral Membrane Protein; Intestines; Investigation; Ion Channel; Knock-out; Life; Lipids; Liquid substance; Lysosomes; Mammals; Maternal antibody; Mediating; Membrane; Methods; Microscopic; Modeling; Molecular; Nematoda; Nutrient; Organelles; Organism; Pathway interactions; Phagocytosis; Phosphotransferases; Process; Proteins; RNA Interference; Regulation; Regulatory Pathway; Relative (related person); Research; Role; Sodium-Hydrogen Antiporter; Surface; System; Technology; Testing; Transgenic Organisms; Transmembrane Transport; Vesicle; absorption; apical membrane; base; biological research; cell type; fetal; human disease; insight; intestinal epithelium; macromolecule; mutant; novel; polarized cell; public health relevance; research study; small molecule; tool; uptake; Affect; Animal Model; Antibodies; Antigens; Apical; Area; Biological Models; Caenorhabditis elegans; Cell Surface Proteins; Cell Surface Receptors; Cell membrane; Cells; Chloride Channels; Clathrin; Complement; Complex; Coupled; Disease; Dysentery; Endocytosis; Endosomes; Enterocytes; Enterotoxins; Epithelial Cells; Excision; Fluids and Secretions; Foundations; Future; Genes; Genetic; Genetic Models; Glucose Transporter; Goals; Homeostasis; Imagery; Integral Membrane Protein; Intestines; Investigation; Ion Channel; Knock-out; Life; Lipids; Liquid substance; Lysosomes; Mammals; Maternal antibody; Mediating; Membrane; Methods; Microscopic; Modeling; Molecular; Nematoda; Nutrient; Organelles; Organism; Pathway interactions; Phagocytosis; Phosphotransferases; Process; Proteins; RNA Interference; Regulation; Regulatory Pathway; Relative (related person); Research; Role; Sodium-Hydrogen Antiporter; Surface; System; Technology; Testing; Transgenic Organisms; Transmembrane Transport; Vesicle; absorption; apical membrane; base; biological research; cell type; fetal; human disease; insight; intestinal epithelium; macromolecule; mutant; novel; polarized cell; public health relevance; research study; small molecule; tool; uptake

DESCRIPTION (provided by applicant): Our goal in this proposal is to identify and understand the cellular components that internalize and transport endocytic cargo from the apical plasma membrane to the lysosomes of intestinal epithelial cells (enterocytes). Many epithelial cell surface receptors, ion channels, and other integral membrane proteins implicated in human disease are specifically localized to the apical membrane. Their steady-state abundance on the apical surface is largely controlled by their relative rates of insertion and removal from the plasma membrane by secretion and endocytosis. To gain new insight into the mechanisms that drive this pathway, we propose to pioneer the use of the microscopic nematode worm C. elegans for these studies. We will take advantage of the unique experimental features of this system, creating a new, highly simplified, and genetically manipulatable paradigm for this research area. Chief among the features that have made C. elegans a leading model organism in nearly all areas of modern biological research are its highly advanced genetics, including extremely facile gene knockdown, knockout, and transgenic technology, coupled with a transparent body that allows visualization of fluorescently tagged molecules in the physiologically relevant context of the intact living organism. Our preliminary studies have already uncovered a novel regulatory pathway controlling apical endocytosis through Rac1/CED-10. Further analysis will dissect the mechanisms by which this pathway controls apical endocytosis. In addition, we plan to apply the unique genetic tools available in C. elegans to identify additional regulators of apical endocytosis conserved with mammals. As the simplest animal model possessing a true intestinal epithelium, C. elegans has the potential to answer key questions regarding the mechanism of apical intestinal function, and can provide a key framework that catalyzes future investigation into the highly related pathways in mammalian intestinal epithelia. PUBLIC HEALTH RELEVANCE. Our goal in this proposal is to identify and understand the cellular components that internalize and transport macromolecules from the apical plasma membrane to the lysosomes of intestinal epithelial cells (enterocytes). Many important proteins implicated in human disease are specifically taken up from the apical membrane by endocytosis, which is specialized in enterocyte cells, and displays important differences from related processes in other types of cells. Thus this research will be relevant to nutrient uptake, fluid homeostasis and dysentery, and fetal antibody transport.

描述（由申请人提供）：我们在此提案中的目标是识别和了解将内吞货物从顶端质膜内部化和运输到肠上皮细胞（肠细胞）的溶酶体的细胞成分。许多涉及人类疾病的上皮细胞表面受体，离子通道和其他综合膜蛋白被特异性地定位于顶端膜。它们在顶部表面上的稳态丰度在很大程度上由它们的相对插入速率和通过分泌和内吞作用从质膜中去除的相对速率控制。为了获得有关驱动这一途径的机制的新见解，我们提议开拓微观线虫蠕虫秀丽隐杆线虫用于这些研究。我们将利用该系统的独特实验特征，为该研究领域创建一个新的，高度简化和遗传操作的范式。在现代生物学研究的几乎所有领域中，使秀丽隐杆线虫成为领先的模型有机体的主要特征是其高级遗传学，包括极其轻松的基因敲低，敲除和转基因技术，再加上透明的身体，可以在生理生物的生理学相关背景下可视化荧光标记的分子。我们的初步研究已经发现了通过RAC1/CED-10控制根尖内吞作用的新型调节途径。进一步的分析将剖析该途径控制顶端内吞作用的机制。此外，我们计划应用秀丽隐杆线虫中可用的独特遗传工具来识别哺乳动物保守的顶端内吞作用的其他调节剂。作为具有真正肠道上皮的最简单动物模型，秀丽隐杆线虫有可能回答有关根尖肠功能机理的关键问题，并可以提供一个关键框架，以促进未来对哺乳动物肠道上皮素中高度相关途径的研究。公共卫生相关性。我们在此提案中的目标是识别和理解将大分子从顶端质膜内部化和转运的细胞成分到肠上皮细胞（肠细胞）的溶酶体。许多与人类疾病有关的重要蛋白质是通过内吞作用专门从顶端膜中特异性吸收的，内吞作用是肠细胞细胞的，并且在其他类型的细胞中显示出与相关过程的重要差异。因此，这项研究将与营养摄取，液体稳态和痢疾以及胎儿抗体转运有关。