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发挥着关键作用，包括在神经和肌肉中。直到最近，cER 似乎存在或不存在，具体取决于细胞类型。这导致了一种传统观点，即 cER 是在某些细胞但不是大多数细胞中发现的静态特化。现在，包括我们实验室的工作在内的各种研究深刻地挑战了这一观点。他们认为，相反，许多（如果不是大多数）动物细胞具有根据适当的生理需求动态产生大量 cER 的固有能力。这意味着存在广泛分布但仍未知的核心机制，可触发 cER 生物发生和周转。我们开发了第一个允许皮质 ER (cER) 受控诱导的系统，并在此建议利用它来剖析产生这种令人着迷但仍然模糊的细胞器的亚细胞途径和分子机制。该系统需要对带有 cER 蛋白（例如酵母 Ist2p 和哺乳动物 STIM1）C 端肽的 ER 膜蛋白进行受控二聚化，从而触发含有这种蛋白的 cER 在通常具有很少或没有 cER 的哺乳动物细胞中增殖。发现这种机制、它产生的途径以及所涉及的分子逻辑是这项研究资助的长期目标，并将对细胞生物学以及神经生理学和肌肉生理学等相关领域的基本概念产生重大影响。