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.

总结 具有适当尺寸的生物管对于大多数主要人体器官的正常功能至关重要 系统（包括但不限于肾脏、肺和血管）。管畸形导致各种 人类疾病，如多囊肾病和血管疾病。果蝇气管是第一个 系统研究管状器官形成的基本机制。 果蝇气管是一个由单层上皮细胞组成的上皮管分支网络 围绕着顶端腔。在输卵管扩张期间，顶端分泌物爆发沉积大量的 腔基质成分的顶端细胞外腔。该过程对于管膨胀至关重要， 获得成熟的尺寸。以前对根尖分泌的研究主要集中在鉴定根尖分泌物的成分上。 囊泡运输途径参与这一过程。正如所料，除了内质网和 高尔基体，一些内体也需要在这个过程中。而不是查明更多的贩运活动 该项目的目标是揭示各种贩运活动的“更广泛的协调”， 成分在顶端分泌。这是以前未被充分认识的顶分泌机制， 果蝇的气管以及整个领域的囊泡贩运。 我们对一个鲜为人知的Osiris（Osi）基因家族的初步研究表明，Osi家族 基因作为“交通协调员”来指导高尔基体后蛋白质的运输。此外，最近的一个同源 检索显示Osi基因与glycoprotein酶1（Glo-1）具有显著的序列同源性。Glo-1很好 已知其在解毒甲基乙二醛（糖酵解的代谢副产物）中的功能。已经 报道Glo-1在囊泡运输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，即它们在肾小管中也可能有一些功能重叠。 机关我们的中心假设是，Osi基因作为“交通协调员”， 分泌相关（例如内体、外泌体）和降解相关运输内的协调变化 组分（例如溶酶体、自噬体）。我们将通过完成以下三个测试来验证这一假设 具体目标：目标。1确定Osi基因在顶腔基质的顶端分泌中的功能， 胀管瞄准2：确定Osi基因作为协调者的功能，以增加数量，体积， 与分泌物相关的贩运成分的活动以牺牲与退化相关的贩运为代价 气管中的成分。瞄准3：鉴定直接与Osi蛋白结合的蛋白质。 该项目意义重大，因为了解各种贩运之间的“更广泛协调” 组分将填补我们对蛋白质运输中的调节层次结构的理解中的差距。