MECHANISMS OF ORGANELLE BIOGENESIS AT THE ENDOPLASMIC RETICULUM SUBDOMAINS

内质网亚域细胞器生物发生机制

• 批准号: 10797317
• 负责人: Amit Joshi
• 金额: $ 24.55万
• 依托单位: UNIVERSITY OF TENNESSEE KNOXVILLE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10797317
• 关键词: Binding; Biogenesis; C2 Domain; Cell Culture Techniques; Cells; Cellular biology; Defect; Disease; Endoplasmic Reticulum; Eukaryota; Eukaryotic Cell; Family; Fatty Liver; Functional disorder; Goals; Integral Membrane Protein; Intracellular Membranes; Life; Lipids; Lipodystrophy; Mammalian Cell; Medical; Membrane; Metabolic Diseases; Mitochondria; Morphology; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Envelope; Organelles; Play; Proteins; Research; Role; Saccharomyces cerevisiae; Testing; Vesicle; Work; Yeasts; Zellweger Syndrome; fatty liver disease; nervous system disorder; peroxisome; therapeutic target

PROJECT SUMMARY Intracellular membrane-bound organelles are a hallmark of all eukaryotic cells. Understanding how cells generate different organelles remains one of the central problems in cell biology. Some organelles, like the endoplasmic reticulum (ER) and mitochondria, are self-generating whereas other organelles can be generated de novo. The ER plays a central role in organelle biogenesis. Even though the ER is a single continuous membrane that extends from the outer nuclear envelope into the periphery of the cell, there are discrete regions in the ER membrane called ER subdomains. Nascent peroxisomes and lipid droplets (LDs) form at specialized ER subdomains. Remarkably, little is known about these ER subdomains and their role in regulating organelle biogenesis. The goal of our research is to determine the mechanisms of peroxisome and LD biogenesis by detailed characterization of the discrete ER subdomains using S. cerevisiae and mammalian cell culture. Previously, we identified a family of reticulon-like ER membrane tubulating proteins, Pex30 in yeasts and multiple C2 domains containing transmembrane proteins, MCTP1 and MCTP2, in higher eukaryotes. We demonstrated that both Pex30 and MCTPs are localized at discrete ER subdomains where nascent pre-peroxisomal vesicles and LDs are formed. Based on these findings, we proposed to identify the proteins and lipids enriched at the specialized ER subdomains using unbiased as well as candidate-based approaches. We will then test the effects of modulating the functions of candidate proteins and lipids on the formation, abundance, morphology, and distribution of peroxisomes and LDs. Investigating the mechanistic details of peroxisomes and LDs biogenesis from these ER subdomains is not only important for understanding basic principles of cell biology but also has critical medical implications. Several life-threatening neurological disorders including Zellweger syndrome associated with peroxisomal defects and metabolic disorders such as type 2 diabetes and fatty liver disease caused due to LD defects have no cure. Determining the mechanisms of organelle biogenesis will have implications in understanding the pathophysiology of these disorders and provide us hints for potential therapeutic targets.

项目总结