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 Preliminary unpublished data identified a cohort of integral membrane signaling proteins that reside in the TGN and are intimately associated with sphingolipid.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“区”组成。 一种起源于内质网，脂肪和蛋白质的合成发生在内质网(ER)，另一种是 包括跨高尔基网络(TGN)、质膜和内切溶酶体系统的细胞器。 TGN膜的脂组成是通过脂转移从早期高尔基体室改变过来的 在内质网(ER)-高尔基体膜将脂质直接输送到TGN膜的蛋白质 接触部位，并由局部鞘磷脂合成，主要为鞘磷脂。因此， TGN被提纯到接近质膜(PM)的水平；它富含鞘脂、胆固醇、 和酸性磷脂，而内质网/高尔基体领域相对缺乏这些脂类，尽管 大多数是在那里生产的。TGN/PM区域的膜是不对称的，鞘磷脂仅限于 仅限于细胞质的表面小叶和酸性甘油磷脂(主要是PS和磷脂酰肌醇) 薄膜传单。关于协调的机制存在着巨大的知识空白 脂类和蛋白质在细胞的两个脂类区域之间的合成和分配。这项研究将 解决这些知识的差距，重点放在高尔基的TRANS和TGN高尔基区。我们会 研究脂转移蛋白在调节细胞膜脂成分中的作用和调节 这些隔间。未发表的初步数据确定了一组完整的膜信号蛋白 它们存在于TGN中，并与鞘脂密切相关。我们将确定其中是否有任何一个 蛋白质作为高尔基体脂稳态的感应器，我们将检验它们调节的假说 将不同的分泌性货物释放到TGN/PM脂类区域。这项研究承诺 阐明有关真核细胞分泌调节的新信息。