Osiris Genes as Novel Coordinators of Protein Trafficking in Drosophila Trachea

Osiris 基因作为果蝇气管蛋白质运输的新协调者

• 批准号: 10291609
• 负责人: Lan Jiang
• 金额: $ 43.9万
• 依托单位: OAKLAND UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10291609
• 关键词: Apical; Autophagosome; Binding; Binding Proteins; Biological; Biological Assay; Biological Models; Blood Vessels; Cessation of life; Co-Immunoprecipitations; Cytoplasmic Vesicles; Defect; Deposition; Disease; Drosophila eye; Drosophila genus; Drug Metabolic Detoxication; Endoplasmic Reticulum; Endosomes; Epithelial; Epithelial Cells; Extracellular Matrix; Gases; Gene Family; Genes; Genetic; Glycocalyx; Glycolysis; Goals; Golgi Apparatus; Human; Image; Immunohistochemistry; Individual; Insecta; Invertebrates; Kidney; Knowledge; Lactoylglutathione Lyase; Lead; Life; Liquid substance; Lung; Lysosomes; Mediating; Metabolic; Morphogenesis; Morphology; Organ; Organism; Pathway interactions; Phenotype; Play; Polycystic Kidney Diseases; Process; Property; Proteins; Pyruvaldehyde; Reporting; Role; Sequence Homology; Shapes; Structure; System; Testing; Time; Trachea; Tube; Tubular formation; Vascular Diseases; Vertebrates; Vesicle; Yeasts; body system; exosome; experimental study; extracellular; gene function; human disease; in vivo; kidney vascular structure; malformation; member; monolayer; mutant; novel; protein transport; secretion process; spine bone structure; trafficking

Summary Biological tubes with appropriate sizes are critical for the proper functioning of most major human organ systems (including but not limited to kidneys, lungs, and blood vessels). Malformation of tubes leads to various human diseases, such as polycystic kidney disease and vascular diseases. Drosophila trachea is the premier system to study the fundamental mechanisms underlying tubular organ formation. The Drosophila trachea is a ramifying network of epithelial tubes with a monolayer of epithelial cells surrounding an apical lumen. During tube expansion, the apical secretion burst deposits large amounts of luminal matrix components to the apical extracellular lumen. This process is critical for tube expansion to acquire mature sizes. Previous studies on apical secretion focused on the identification of components of the vesicular trafficking pathway involved in this process. As expected, in addition to endoplasmic reticulum and Golgi, a few endosomes are also required in this process. Instead of identifying additional trafficking components, the objective of this project is to reveal the “broader coordination” of various trafficking components during apical secretion. This is a previously underappreciated mechanism in apical secretion in Drosophila trachea as well as in the overall field of vesicular trafficking. Our preliminary study on a poorly understood Osiris (Osi) gene family strongly indicates that Osi family genes function as “traffic coordinators” to direct post-Golgi protein trafficking. In addition, a recent homology search revealed that Osi genes share noticeable sequence homology to glyoxalase 1 (Glo-1). Glo-1 is well known for its function in detoxification of methylglyoxal, a metabolic byproduct of glycolysis. It has been reported that Glo-1 plays a role in vesicular trafficking as well as morphological changes in blood vessels. These discoveries lead to a plausible hypothesis that they may also have some functional overlap in tubular organs. Our central hypothesis is that Osi genes function as “traffic coordinators” to direct apical proteins by coordinated changes within secretion-related (e.g. endosomes, exosomes) and degradation-related trafficking components (e.g. lysosomes, autophagosomes). We will test this hypothesis by completing the following three specific aims: Aim. 1 Determine the function of Osi genes in apical secretion of the apical luminal matrix during tube expansion. Aim. 2: Determine the function of Osi genes as coordinators to increase numbers, volumes, activities of secretion-related trafficking components at the expense of degradation-related trafficking components in trachea. Aim. 3: Identify proteins that directly bind to Osi proteins. This project is significant because understanding the “broader coordination” between various trafficking components will fill the gap in our understanding of the regulatory hierarchy in protein trafficking.

概括 适当尺寸的生物管对于大多数主要人体器官的正确功能至关重要 系统（包括但不限于肾脏，肺和血管）。管的畸形导致各种 人类疾病，例如多囊性肾脏疾病和血管疾病。果蝇气管是总理 研究结核病的基本机制的系统。 果蝇气管是一个具有上皮细胞单层的上皮管网络 围绕顶端管腔。在膨胀期间，顶端分泌爆发大量沉积 口腔基质组件到顶部细胞外管腔。这个过程对于扩展到 获取成熟尺寸。先前关于顶端分泌的研究重点是鉴定成分 囊泡贩运途径涉及此过程。不出所料，除了内质网和 在此过程中，Golgi，也需要一些内体。而不是确定额外的贩运 组件，该项目的目的是揭示各种贩运的“更广泛的协调” 顶端分泌过程中的成分。这是先前在顶端分泌中的未经被评估的机制 果蝇气管以及囊泡贩运的整体领域。 我们对较知之不书的Osiris（OSI）基因家族的初步研究强烈表明OSI家族 基因充当“交通协调员”，可指导高尔基蛋白运输后。此外，最近的同源性 搜索表明，OSI基因与乙二醛酶1（GLO-1）共享明显的序列同源性。 glo-1很好 以其在甲基乙二醇排毒（一种糖酵解的代谢副产品）中的功能而闻名。它一直 报道GLO-1在囊泡贩运以及血管的形态变化中起作用。 这些发现导致了一个合理的假设，即它们在管状中也可能有一些功能重叠 器官。我们的中心假设是OSI基因作为“交通协调员”的作用，以指导顶端蛋白 与分泌有关（例如内体，外泌体）和与退化有关的贩运的协调变化 成分（例如溶酶体，自噬体）。我们将通过完成以下三个来检验这一假设 具体目的：目标。 1确定OSI基因在顶端腔矩阵的顶端分泌中的功能 管扩展。目的。 2：确定OSI基因作为协调员的功能，以增加数量，体积， 与分泌有关的贩运组件的活动，以牺牲与退化有关的贩运 气管中的组件。目的。 3：鉴定直接与OSI蛋白结合的蛋白质。 该项目很重要，因为了解各种贩运之间的“更广泛的协调” 组件将填补我们对蛋白质运输中调节性层次结构的理解的空白。