Co-translational Regulation in the Vasculature of Organ Systems with Aging

衰老过程中器官系统脉管系统的共翻译调节

• 批准号: 10738940
• 负责人: PAUL H GOLDSPINK
• 金额: $ 23.99万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10738940
• 关键词: Adult; Affinity Chromatography; Age; Aging; Basic Science; Blood capillaries; Cardiovascular Diseases; Cardiovascular system; Cell Communication; Cell Line; Cell Separation; Cell model; Cells; Characteristics; Complex; Coronary; Coupling; Data; Data Set; Development; Diagnosis; Embryonic Development; Endothelial Cells; Endothelium; Environment; Enzymes; Eukaryotic Cell; Event; Gender; Gene Expression; Genetic Transcription; Genomics; Goals; Gonadal Steroid Hormones; Growth; Heart; Hypertension; Impairment; Investigation; Knowledge; Label; Life; Ligands; Maintenance; Mammalian Cell; Mediating; Mediator; Messenger RNA; Molecular; Molecular Chaperones; Myocardial Infarction; Neonatal; Organ; Organism; Pathologic; Pathology; Pathway interactions; Physiological; Play; Polyribosomes; Post-Translational Protein Processing; Post-Translational Regulation; Process; Production; Prokaryotic Cells; Proteins; Proteome; Proteomics; Regulation; Ribosomes; Role; Scheme; Shapes; Signal Pathway; Signal Transduction; Stimulus; Stress; Stroke; System; Technology; Testing; Transcript; Translating; Translational Regulation; Translations; Yeasts; age related; angiogenesis; body system; cardiovascular injury; cell type; gender difference; genetic manipulation; genetic regulatory protein; in vivo; innovation; intercellular communication; mRNA Translation; novel; polypeptide; postnatal; proteostasis; receptor; response; response to injury; sex; transcriptome; transcriptomics; wound healing

Project Summary/Abstract The production of functional proteins is a multistep process whereby newly synthesized polypeptides are enzymatically processed, folded, and assembled into oligomeric complexes. Key maturation processes occur co-translationally by coupling mRNA translation and nascent protein maturation on the ribosomes, assisted by a network of regulatory proteins. Despite decades of basic research, our understanding of co-translational processes is shaped predominantly by genetic manipulations in prokaryotic and eukaryotic cell models, but limited data exists in cells from intact mammalian physiological systems. To overcome this hurdle, this project aims to develop a comprehensive understanding of co-translational regulation of nascent proteins as they reach their functional state within the angiogenic signaling pathways of the endothelium in the heart during aging. We have recently developed an approach and tested the potential for simultaneous isolation of proteins present within the actively translating polyribosome/mRNA complexes within the endothelium of the heart. State-of-the-art multiplex labelling and quantification of these proteins has permitted the identification of concordant and discordant regulated cell-specific pathways based on actively translating mRNA and protein profiles associated with the endothelial stress. Leveraging this innovative advancement in “functional co- translatomics”, we aim to study the changes in co-translational complexes within endothelial cell angiogenic ligand-receptor and cell-cell interaction signaling networks within the aging heart. In Aim 1 , we will define changes in the co-translational regulation of concordantly regulated angiogenic signaling pathways during neonatal and adult life with aging and gender. In Aim 2 , we will define the post-translational modifications of proteins within discordantly regulated angiogenic signaling pathways which may contribute to the impairment angiogenesis in the heart during aging. Ultimately this knowledge could aid in the development of more effective means for diagnosing and treating the impairment of angiogenesis that occurs with aging and predisposes the heart to cardiovascular disease and injury.

项目概要/摘要 功能性蛋白质的生产是一个多步骤的过程，其中新合成的 多肽经过酶处理、折叠并组装成寡聚复合物。钥匙 成熟过程通过 mRNA 翻译和新生蛋白质的耦合发生共翻译 在调节蛋白网络的协助下，在核糖体上成熟。尽管几十年来 基础研究中，我们对共翻译过程的理解主要是由 原核和真核细胞模型中的遗传操作，但细胞中存在有限的数据 来自完整的哺乳动物生理系统。为了克服这一障碍，该项目旨在 全面了解新生蛋白质的共翻译调节 在内皮细胞的血管生成信号通路中达到其功能状态 衰老过程中的心脏。我们最近开发了一种方法并测试了其潜力 同时分离主动翻译的多核糖体/mRNA中存在的蛋白质 心脏内皮内的复合物。最先进的多重标记和 这些蛋白质的定量可以识别一致和不一致的蛋白质 基于主动翻译 mRNA 和蛋白质谱来调节细胞特异性途径 与内皮应激有关。利用“功能性协同”方面的这一创新进步 翻译组学”，我们的目标是研究内皮细胞内共翻译复合物的变化 衰老心脏内的血管生成配体受体和细胞间相互作用信号网络。在 目标1 ，我们将定义协调监管的协同翻译监管的变化 新生儿和成人生命中随年龄和性别变化的血管生成信号通路。在 目标2 ， 我们 将定义不协调调节的血管生成中蛋白质的翻译后修饰 可能导致心脏血管生成受损的信号通路 老化。最终，这些知识可以帮助开发更有效的手段 诊断和治疗随衰老而发生的血管生成障碍 心脏容易发生心血管疾病和损伤。