Neuroprotective actions of cystathionine g-lyase through gasotransmitter hydrogen sulfide signaling

胱硫醚 G-裂解酶通过气体递质硫化氢信号传导的神经保护作用

• 批准号: 10614053
• 负责人: Bindu Paul
• 金额: $ 67.35万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10614053
• 关键词: 3-Mercaptopyruvate sulfurtransferase; 3xTg-AD mouse; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease therapeutic; Alzheimer’s disease biomarker; Amino Acids; Antioxidants; Behavior; Biological Assay; Brain; Brain region; Cell Line; Cell physiology; Cells; Central Nervous System; Cystathionine; Cystathionine beta-Synthase; Cysteine; Cysteine Desulfhydrase; Cysteine Metabolism Pathway; Development; Disease; Enzymes; Equilibrium; Generations; Glutathione; Goals; Hippocampus; Huntington Disease; Hydrogen Sulfide; Immunohistochemistry; Impairment; Inflammation; Learning; Lyase; Maintenance; Maps; Mediating; Memory; Metabolism; Methods; Mitochondria; Modification; Molecular; Monitor; Motor; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Nitric Oxide; Oxidation-Reduction; Oxidative Stress; Parkinson Disease; Pathology; Pathway interactions; Physiological; Physiological Processes; Post-Translational Protein Processing; Precision therapeutics; Prodrugs; Production; Proteins; Regulation; Research Personnel; Role; SKIL gene; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Supplementation; Testing; Wild Type Mouse; age related; age related neurodegeneration; behavior test; biological adaptation to stress; biomarker development; dimedone; enzyme activity; interest; mouse model; multidisciplinary; neuroprotection; neurotransmission; novel therapeutics; nuclear factor-erythroid 2; prevent; response; sulfhydration; therapeutic target

PROJECT SUMMARY Neuroprotective actions of cystathionine γ-lyase through gasotransmitter hydrogen sulfide signaling. Hydrogen sulfide (H2S) is a gaseous signaling molecule or gasotransmitter which serves key roles in the central nervous system. However, specific targets and mechanisms of H2S action in the brain are obscure. Herein, we propose to elucidate the signaling pathways modulated by H2S in the brain that are neuroprotective to arrive at therapeutics targeting Alzheimer's disease (AD). H2S is generated from the amino acid cysteine which, in turn, is synthesized by cystathionine γ-lyase (CSE) via the transsulfuration pathway in the brain. H2S is also synthesized by two other enzymes, cystathionine β-synthase (CBS) and 3- mercaptopyruvate sulfurtransferase (3-MST), in the brain. We have demonstrated previously, that H2S and cysteine metabolism are dysregulated in AD. One of the modes by which H2S signals is via a posttranslational modification termed sulfhydration or persulfidation, wherein the reactive –SH group of cysteine residues on target proteins is converted to an –SSH group in a fashion analogous to nitrosylation by nitric oxide (NO), where the –SH groups are converted to –SNO groups. Although sulfhydration and nitrosylation modulate diverse physiological processes ranging from response to inflammation to neuroprotection, the molecular mechanisms by which cysteine and H2S/NO axes of gasotransmitter signaling affect neuronal function are yet to be deciphered. In Aim 1 of this project, we will monitor expression and activity of the three H2S biosynthetic enzymes, CSE, CBS and 3-MST in the mouse brain at various ages. Sulfhydration status in normal as well as mice lacking CSE will be assessed. The specific proteins modified by sulfhydration will be identified, and sites of sulfhydration mapped on them. The interplay of sulfhydration with nitrosylation in neuronal function will be monitored. In Aim 2, we will analyze the involvement of H2S in stress responses and behavior. In Aim 3, we will identify differentially sulfhydrated proteins in the 3xTg-AD mouse model of AD. By studying the function of CSE and H2S in the brain, we set a goal to better understand signaling mediated by cysteine, H2S and protein sulfhydration in the context of neuronal signaling in AD. Understanding the regulation of H2S signaling in the brain helps to determine the basic physiological pathways involved in neuroprotection and pins down the nodes for precision therapeutics and development of biomarkers for AD and other age-related neurodegenerative diseases involving dysregulated H2S signaling. 1

项目摘要 胱硫醚γ-裂解酶通过气体递质硫化氢的神经保护作用 信号 硫化氢（H2S）是一种气体信号分子或气体传递物，其在生物体内起关键作用。 中枢神经系统然而，H2S在脑中作用的具体靶点和机制尚不清楚。 在此，我们建议阐明H2S在大脑中调节的信号通路， 神经保护的研究，以达到针对阿尔茨海默病（AD）的治疗。H2S由氨基生成 酸性半胱氨酸，由胱硫醚γ-裂解酶（CSE）通过转硫途径合成 在大脑中。H2S也由另外两种酶合成，即胱硫醚β-合酶（CBS）和3- 巯基丙酮酸硫转移酶（3-MST）。我们之前已经证明，H2S和 半胱氨酸代谢在AD中失调。H2S信号传导的模式之一是通过翻译后修饰。 修饰被称为硫化或过硫化，其中半胱氨酸残基上的反应性-SH基团 靶蛋白以类似于通过一氧化氮（NO）的亚硝基化的方式转化为-SSH基团， 其中-SH基团转化为-SNO基团。虽然巯基化和亚硝基化调节 从炎症反应到神经保护的多种生理过程， 半胱氨酸和H2S/NO轴的气体递质信号影响神经元功能的机制是 还没有被破译在本项目的目标1中，我们将监测三种H2S的表达和活性， 生物合成酶，CSE，CBS和3-MST在不同年龄的小鼠脑中。硫酸化状态 评估正常以及缺乏CSE的小鼠。通过巯基化修饰的特定蛋白质将被 并在其上绘制了硫化地点的地图。巯基化与亚硝基化的相互作用， 将监测神经元功能。在目标2中，我们将分析H2S在应激反应中的参与 和行为。在目标3中，我们将鉴定3xTg-AD小鼠模型中的差异性巯基化蛋白质， AD. 通过研究CSE和H2S在大脑中的功能，我们设定了一个目标，以更好地理解信号传导 在AD中神经元信号传导的背景下，由半胱氨酸、H2S和蛋白质巯基化介导。理解 H2S信号在大脑中的调节有助于确定参与的基本生理途径， 神经保护，并为精确治疗和AD生物标志物的开发确定节点 以及涉及H2S信号传导失调的其他年龄相关的神经变性疾病。 1