Lipid Dynamics in the Golgi Apparatus

高尔基体中的脂质动力学

• 批准号: 10330746
• 负责人: Christopher G Burd
• 金额: $ 50.85万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10330746
• 关键词: Address; Alzheimer' s Disease; Cardiovascular Diseases; Cell membrane; Cells; Cholesterol; Data; Defect; Diabetes Mellitus; Endoplasmic Reticulum; Eukaryotic Cell; Glycerophospholipids; Golgi Apparatus; Homeostasis; Knowledge; Lead; Lipids; Malignant Neoplasms; Membrane; Membrane Lipids; Organelles; Pathway interactions; Phosphatidylinositols; Phospholipids; Protein Biosynthesis; Proteins; Regulation; Research; Research Project Grants; Role; Signaling Protein; Site; Sphingolipids; Sphingomyelins; System; Testing; cohort; lipid transfer protein; nervous system disorder; protein function; sensor; trans-Golgi Network

The organelle membrane system of the eukaryotic cell is constituted by two complementary lipid `territories'. One originates from the endoplasmic reticulum (ER), where lipid and protein synthesis occurs, and the other is encompasses the trans-Golgi network (TGN), plasma membrane, and organelles of endo-lysosomal system. The lipid composition of TGN membrane is modified from that of earlier Golgi compartments by lipid transfer proteins that deliver lipids directly to TGN membrane at the endoplasmic reticulum (ER)-Golgi membrane contact site, and from local sphingolipid synthesis, principally sphingomyelin. Hence the composition of the TGN is refined to approximate that of the plasma membrane (PM); it is enriched in sphingolipid, cholesterol, and acidic phospholipids, while the ER/Golgi territory is relatively deficient of these lipid classes, even though most are produced there. Membrane of the TGN/PM territory is asymmetric, with sphingolipids restricted to the exofacial leaflet and acidic glycerophospholipids (chiefly PS and phosphoinositides) restricted to cytoplasmic membrane leaflets. There are expansive gaps of knowledge regarding the mechanisms that coordinate the synthesis and distribution of lipids and proteins between the two lipid territories of the cell. This research will address these gaps of knowledge, focusing on the trans and TGN Golgi compartments of the Golgi. We will investigate the roles and regulation of lipid transfer proteins that modify the membrane lipid composition of these compartments. Preliminary unpublished data identified a cohort of integral membrane signaling proteins that reside in the TGN and are intimately associated with sphingolipid. We will determine if any of these proteins function as sensors of Golgi lipid homeostasis, and we will test a hypotheses that they regulate release of distinct cohorts of secretory cargo into the TGN/PM lipid territory. This research promises to elucidate new information regarding the regulation of secretion by eukaryotic cells.

真核细胞的细胞器膜系统由两个互补的脂质“领域”构成。 一种起源于内质网（ER），在那里发生脂质和蛋白质合成，另一种是 包括高尔基体网络（trans-Golgi network，TGN）、质膜和内-溶酶体系统的细胞器。 TGN膜的脂质组成通过脂质转移而从早期的高尔基体室改变 在内质网（ER）-高尔基体膜处将脂质直接递送至TGN膜的蛋白质 接触部位，并从局部鞘脂合成，主要是鞘磷脂。因此， TGN被精炼为接近质膜（PM）的TGN;它富含鞘脂、胆固醇， 和酸性磷脂，而ER/高尔基体领域相对缺乏这些脂质类，即使 大多数都是在那里生产的。TGN/PM区域的膜是不对称的，鞘脂局限于膜上。 外表面小叶和酸性甘油磷脂（主要是PS和磷酸肌醇）仅限于细胞质 膜小叶。关于协调这些活动的机制，存在着巨大的知识空白。 在细胞的两个脂质区域之间的脂质和蛋白质的合成和分布。这项研究将 解决这些知识的差距，专注于高尔基体的反式和TGN高尔基室。我们将 研究脂质转移蛋白的作用和调节，改变膜脂质组成， 这些隔间。初步未发表的数据确定了一组完整的膜信号蛋白 存在于TGN中并与鞘脂密切相关。我们将确定是否有任何这些 蛋白质作为高尔基体脂质稳态的传感器，我们将测试一个假设，它们调节 释放不同的分泌物进入TGN/PM脂质领域。这项研究承诺， 阐明关于真核细胞分泌调节的新信息。