Cortical ER Biogenesis in Mammalian Cells

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关键作用，包括神经和肌肉。直到最近，cER似乎存在或不存在，这取决于细胞类型。这导致了传统的观点，即cER是在一些但不是大多数细胞中发现的静态特化。现在，各种各样的研究，包括我们实验室的工作，深刻地挑战了这一观点。他们表明，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，触发cER生物发生和营业额。我们已经开发出第一个系统，允许皮质ER（cER）的控制诱导，并建议在这里利用它来解剖亚细胞途径和分子机制，产生这个迷人的，但仍然模糊的细胞器。该系统需要携带来自cER蛋白的C-末端肽的ER膜蛋白的受控二聚化，例如酵母Ist 2 p和哺乳动物STIM 1，其在通常具有很少或没有cER的各种哺乳动物细胞中触发含有该蛋白的cER的增殖。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。

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.