Studies on the impact of acetyl-cysteine on metabolism

乙酰半胱氨酸对代谢影响的研究

• 批准号: 10574934
• 负责人: Matthew D Hirschey
• 金额: $ 23.51万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10574934
• 关键词: Ablation; Acceleration; Acetyl Coenzyme A; Acetylation; Acetylcysteine; Acetyltransferase; Acyl Coenzyme A; Adipose tissue; Affect; Age; Aging; Amides; Applications Grants; Automobile Driving; Biochemical; Biological; Biological Assay; Biological Process; Biology; Blood; Brain; Brown Fat; Cell physiology; Cells; Chemicals; Chemistry; Chromatin; Cysteine; Data; Detection; Development; Disease; Dithiothreitol; Drug or chemical Tissue Distribution; Elements; Excision; Fasting; Gender; Gene Expression; Generations; Glutathione Reductase; Goals; Harvest; Health; Heart; Histones; Homeostasis; In Vitro; Knowledge; Liver; Lysine; Mass Spectrum Analysis; Measures; Mediator; Metabolic; Metabolic Control; Metabolism; Methods; Mitochondria; Modeling; Modification; Mus; Nutrient; Oxidation-Reduction; Peptides; Pharmaceutical Preparations; Phenotype; Physiological; Play; Post-Translational Protein Processing; Posttranslational Amino Acid Modification; Preparation; Prevalence; Process; Proline Dehydrogenase; Protein Acetylation; Proteins; Proteome; Proteomics; Public Health; Reaction; Regulation; Role; Running; Sampling; Series; Side; Signal Transduction; Site; Skeletal Muscle; Skin; Source; Surveys; Tissues; Wild Type Mouse; Work; detection of nutrient; experimental study; feeding; innovation; novel; nutrient metabolism; preservation; prevent; protein function; response; sensor; therapeutically effective; thioester; treatment strategy; tris(2-carboxyethyl)phosphine

Cells integrate nutrient sensing and metabolism to coordinate proper cellular responses to a particular nutrient source. One way this occurs is via post-translational modifications of proteins. Acetyl-lysine is among the most studied modification and regulates dynamic processes ranging from chromatin and gene expression to metabolism. Our preliminary data presented in this application expand upon the acetylation landscape and describe a new protein modification called acetyl-cysteine. This modification is abundant across the proteome and is enriched on proteins involved in metabolism. These early data reveal key gaps in our understanding of the acetylation landscape: what is the tissue distribution of this new modification? Under which physiological conditions does this modification change? Which proteins are modified? What is the cellular consequence of cysteine hyperacetylation? Is this relevant for aging? There is a critical need to understand the full range of protein modifications in order to better understand physiological nutrient sensing and how it is perturbed in the setting of disease. Although it is widely accepted that lysine modifications can participate in intracellular nutrient sensing and is dysregulated with aging, no data exists on acetyl-cysteine. Therefore, the single objective of this exploratory grant application is to determine the site(s), consequences, and physiologic mediators of cysteine acetylation. Aim 1 will investigate the prevalence of cysteine acetylation by tissue type and metabolic state. In a complementary parallel approach, Aim 2 will characterize the effects of cysteine acetylation on protein activity. This project is significant because it uncovers a previously overlooked protein modification. Furthermore, given cysteine’s central role in redox homeostasis, it is poised to play a central role in metabolic homeostasis. We put forth conceptual and technical innovations that will both follow directed hypotheses and allow unbiased discovery of the most important aspects of this new protein modification. Successful completion of this project will reveal a new aspect of intracellular signaling and metabolic homeostasis that could influence our understanding of redox biology and metabolism during aging.

细胞整合了营养感的感应和代谢，以协调对特定营养素的适当细胞反应 来源。发生这种情况的一种方法是通过蛋白质的翻译后修饰。乙酰赖氨酸是最大的 研究了修饰并调节从染色质和基因表达到的动态过程 代谢。我们在本应用程序中介绍的我们的初步数据扩展了乙酰化景观和 描述一种称为乙酰 - 半胱氨酸的新蛋白质修饰。在蛋白质组中，这种修饰很丰富 并富含参与代谢的蛋白质。这些早期数据揭示了我们对 乙酰化景观：这种新修饰的组织分布是什么？在哪个生理学下 条件这种修改会改变吗？哪些蛋白被修饰？什么是细胞的结果 半胱氨酸高乙酰化？这与衰老有关吗？迫切需要了解的全部范围 蛋白质修饰是为了更好地理解物理营养敏感性及其在如何扰动中 疾病的设置。尽管赖氨酸的修饰可以参与细胞内营养素已被广泛接受 传感并因衰老而失调，乙酰甲基半胱氨酸不存在数据。因此，这个目标的一个目标 探索性赠款的应用是确定半胱氨酸的部位，后果和生理介体 乙酰化。 AIM 1将研究组织类型和代谢状态的半胱氨酸乙酰化的患病率。在 AIM 2完全平行的方法将表征半胱氨酸乙酰化对蛋白活性的影响。 该项目很重要，因为它会发现先前被忽略的蛋白质修饰。此外，给予 CySteine在氧化还原稳态中的中心作用，在代谢稳态中发挥核心作用是中毒的。我们放了 第四个概念和技术创新将遵循指示假设并允许无偏见的发现 这种新蛋白质修饰的最重要方面。该项目的成功完成将揭示 细胞内信号传导和代谢稳态的新方面，可能会影响我们对氧化还原的理解 衰老期间的生物学和代谢。