Lipid Dynamics in the Golgi Apparatus

高尔基体中的脂质动力学

• 批准号: 10552618
• 负责人: Christopher G Burd
• 金额: $ 71.12万
• 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/10552618
• 关键词: 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; Sorting; 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 Preliminary unpublished data identified a cohort of integral membrane signaling proteins that reside in the TGN and are intimately associated with sphingolipid.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“区域”构成。 一种起源于内质网（ER），脂质和蛋白质在此合成，另一种来自内质网（ER）。 包括跨高尔基体网络 (TGN)、质膜和内溶酶体系统的细胞器。 TGN 膜的脂质成分是通过脂质转移从早期高尔基室的脂质成分中改变的 将脂质直接递送至内质网 (ER)-高尔基膜上的 TGN 膜的蛋白质 接触位点，并且来自局部鞘脂合成，主要是鞘磷脂。因此，组成 TGN 被细化以接近质膜 (PM) 的值；它富含鞘脂、胆固醇、 和酸性磷脂，而 ER/高尔基体区域相对缺乏这些脂质类别，尽管 大多数是在那里生产的。 TGN/PM 区域的膜是不对称的，鞘脂仅限于 面外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。关于协调机制的知识存在巨大差距 细胞两个脂质区域之间脂质和蛋白质的合成和分布。这项研究将 解决这些知识空白，重点关注高尔基体的反式和 TGN 高尔基体室。我们将 研究改变膜脂质组成的脂质转移蛋白的作用和调节 这些隔间。初步未发表的数据确定了一组整合膜信号蛋白 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 蛋白质充当高尔基体脂质稳态的传感器，我们将测试它们调节的假设 将不同的分泌货物释放到 TGN/PM 脂质区域。这项研究有望 阐明有关真核细胞分泌调节的新信息。