肌浆网/内质网脂质稳态和膜接触的新颖调节因子

Endoplasmic reticulum (ER) represents the largest membrane constituents of bio-membrane systems. ER membrane integrity and lipid homeostasis play vital roles in numerous cellular processes. ER exchange various substances with other organelles via transport vesicles or membrane contacts. The latter mechanism, though less understood, is particularly important in funneling lipids and small molecules. Terminally differentiated muscle cells contain specialized endoplasmic reticulum (sarcoplasmic reticulum, SR), which forms extensive membrane contacts with the plasma membrane and mitochondria, respectively. These structures provide maximal support for exercise and metabolic functions of muscle, and represent a unique system to study membrane contacts and their physiological roles. Our preliminary studies found that SAR1B, a key regulator of ER membrane dynamics, is highly enriched in skeletal muscle. Muscle specific SAR1B knockout mice showed muscle damage and impaired activity. Further work suggest that SAR1B may be a novel regulator to recruit yet-to-be identified downstream factors, in the maintenance of endo-membrane lipid homeostasis as well as membrane contacts between SR and mitochondria. We propose to combine mouse models, mass spectrometry and imaging techniques, as well as CRISPR-based gene editing approaches, to unravel the mechanisms by which SAR1B regulates ER lipid homeostasis and membrane contacts and to explore their implication in mitochondria related muscle diseases.

内质网是细胞中最大的内膜系统，其结构和脂质稳态对细胞功能至关重要。内质网通过膜泡运输及膜接触的方式，与多种细胞器互通有无。膜接触对脂质及小分子的交换尤为重要，也存在诸多未知。终端分化的骨骼肌细胞拥有特化的内质网结构（肌浆网）及发达的膜接触，为肌肉运动、代谢提供最大化支持，也是解析膜接触的独特系统。在前期工作中，我们发现定位于内质网表面、调节膜动态的关键蛋白SAR1B高度富集在肌肉组织中，且骨骼肌特异敲除SAR1B的小鼠模型发生了肌肉病变及运动功能衰退。进一步的研究提示了SAR1B或作为调节内膜系统脂质稳态、维持肌浆网-线粒体膜接触的功能蛋白，并可能招募新颖的下游因子来参与调节肌肉生理。以此为基础，本课题将综合使用动物模型、定量质谱及成像技术、和包括CRISPR在内的分子生物学手段，深入研究SAR1B特异调节内质网脂质稳态及膜接触的机理，并且探索SAR1B在线粒体、肌肉疾病中的潜在作用。

内质网是细胞中最大的内膜系统，其结构和脂质稳态对细胞功能至关重要。内质网通过膜泡运输及膜接触的方式，与多种细胞器互通有无。膜接触对脂质及小分子的交换尤为重要，也存在诸多未知。终端分化的骨骼肌细胞拥有特化的内质网结构（肌浆网）及发达的膜接触，为肌肉运动、代谢提供最大化支持，也是解析膜接触的独特系统。在前期工作中，我们发现定位于内质网表面、调节膜动态的关键蛋白SAR1B高度富集在肌肉组织中，且骨骼肌特异敲除SAR1B的小鼠模型发生了肌肉病变及运动功能衰退。在本项目的支持下，我们进一步的研究发现，SAR1B是调节内膜系统脂质稳态、维持肌浆网-线粒体膜接触的功能蛋白；并综合使用动物模型、定量质谱及成像技术、和包括CRISPR在内的分子生物学手段，深入研究了SAR1B特异调节内质网脂质稳态及膜接触的机理，并且探索SAR1B在线粒体、肌肉疾病中的潜在作用。