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.

项目摘要/摘要 功能蛋白的产生是一个多步过程，新合成 多肽是酶促处理，折叠和组装成寡聚复合物的。钥匙 成熟过程通过耦合mRNA翻译和新生蛋白共译 核糖体上的成熟，在调节蛋白网络的帮助下。尽管数十年 基础研究，我们对共译过程的理解主要由 原核生物和真核细胞模型中的遗传操作，但是细胞中存在有限的数据 来自完整的哺乳动物物理系统。为了克服这一障碍，该项目旨在 对新生蛋白的共同调节进行全面了解 在内皮的血管生成信号通路内达到其功能状态 衰老期间的心。我们最近开发了一种方法，并测试了 在积极翻译多核糖体/mRNA中存在的蛋白质的简单隔离 心脏内皮内的复合物。最先进的多重标签和 这些蛋白质的数量允许鉴定一致性和不一致 基于主动翻译mRNA和蛋白质曲线的调节细胞特异性途径 与内皮压力相关。利用这种创新的进步在功能共同的共同体中 翻译学”，我们旨在研究内皮细胞内共晶络合物的变化 衰老心脏内的血管生成配体受体和细胞 - 细胞相互作用信号网络。在 目标1 ，我们将定义一致调节的共同调节的变化 新生儿和成人生活中的血管生成信号通路，具有衰老和性别。 目标2 ， 我们 将定义不一致的血管生成中蛋白质的翻译后修饰 信号传导途径可能导致心脏损伤的血管生成。 老化。最终，这种知识可以帮助发展更有效的手段 诊断和治疗随着衰老和易感性而发生的血管生成损伤 心血管疾病和伤害的心脏。