Cortical ER Biogenesis in Mammalian Cells

哺乳动物细胞中的皮质 ER 生物发生

• 批准号: 8653580
• 负责人: JAMES ROTHMAN
• 金额: $ 33.3万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8653580
• 关键词: Animals; Area; Biochemical; Biochemical Genetics; Biogenesis; C-terminal; Candidate Disease Gene; Cell Cycle; Cell membrane; Cells; Cellular biology; Coat Protein Complex I; Complex; Development; Dimerization; Electron Microscope; Endoplasmic Reticulum; Foundations; Future; Gene Proteins; Genes; Genetic; Goals; Golgi Apparatus; Laboratories; Life; Light; Logic; Mammalian Cell; Membrane Proteins; Microtubule-Associated Proteins; Microtubules; Molecular; Muscle; Nerve; Organelles; Pathway interactions; Peptides; Physiological; Physiological Processes; Physiology; Play; Process; Proteins; Research Project Grants; Role; Route; SNAP receptor; STIM1 gene; Specific qualifier value; Staging; System; Time; Work; Yeasts; base; cell fixing; cell type; dimer; fascinate; knock-down; neurophysiology; novel; optical imaging; tomography

DESCRIPTION (provided by applicant): The cortical ER (cER) plays a critical role in many important physiological processes in the body, including in nerve and muscle. Until recently, cER seemed to be either present or absent, depending on the cell type. This has led to the traditional view that cER is a static specialization found in some but not most cells. Now a variety of studies, including work from our laboratory, profoundly challenge this view. They suggest that - to the contrary - many if not most animal cells have the inherent capacity to dynamically produce cER in copious quantities upon suitable physiologic demand. This implies the existence of broadly-distributed yet still unknown core machinery that triggers cER biogenesis and turnover. We have developed the first system that permits the controlled induction of cortical ER (cER) and propose here to utilize it to dissect the sub-cellular pathways and molecular mechanisms that produce this fascinating but still obscure organelle. The system entails controlled dimerization of ER membrane proteins bearing the C-terminal peptide from a cER protein, such as yeast Ist2p and mammalian STIM1, which triggers proliferation of cER containing this protein in various mammailian cells that normally have little or no cER. Discovering this machinery, the pathways it generates, and the molecular logic involved is the long-term goal of this research grant, and will have a major impact on fundamental concepts in cell biology and related areas of neurophysiology and muscle physiology, among others.

描述（由申请人提供）：皮质ER（CER）在体内许多重要的生理过程中起着至关重要的作用，包括神经和肌肉。直到最近，根据细胞类型，CER似乎是存在的或不存在的。这导致了传统观点，即CER是在某些但不是大多数细胞中发现的静态专业化。现在，各种研究，包括我们实验室的工作，深刻地挑战了这一观点。他们认为 - 相反，许多动物细胞（如果不是大多数动物细胞）具有固有的能力，可以在适当的生理需求下动态生产大量的CER。这意味着存在广泛分布但仍然未知的核心机制，这些机制触发了CER生物发生和离职。我们开发了第一个允许受控诱导皮质ER（CER）的系统，并在此处提议利用它来剖析产生这种迷人但仍然晦涩的细胞器的亚细胞途径和分子机制。该系统需要从CER蛋白（例如酵母菌IST2P和哺乳动物stim1）中携带C末端肽的ER膜蛋白的二聚化，从而触发了通常几乎没有CER的各种哺乳动物细胞中含有该蛋白质的CER的增殖。发现这种机械，其产生的途径以及所涉及的分子逻辑是该研究赠款的长期目标，将对细胞生物学和神经生理学和肌肉生理学的基本概念以及其他相关领域产生重大影响。