Epigenetic Mechanisms Regulating Chronic Intermittent Hypoxia-evoked Sympathetic Activation

调节慢性间歇性缺氧引起的交感神经激活的表观遗传机制

• 批准号: 9914158
• 负责人: Jayasri Nanduri
• 金额: $ 48.69万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9914158
• 关键词: Acetylation; Area; Autonomic Dysfunction; Binding; Biochemical; Cell Culture Techniques; Chronic; Complex; DNA; DNA Methylation; DNA Modification Methylases; Data; Disease Progression; EP300 gene; Epigenetic Process; Equilibrium; Exhibits; Exposure to; Gene Expression; Genes; Genetic Transcription; Goals; HDAC3 gene; HDAC5 gene; Histone Acetylation; Histone Deacetylase; Histones; Hypertension; Hypoxia; Hypoxia Inducible Factor; Joints; Link; Lysine; Mediating; Molecular; Mus; PC12 Cells; Pathology; Pathway interactions; Phenotype; Pheochromocytoma; Physiological; Play; Post-Translational Protein Processing; Procollagen-Proline Dioxygenase; Proteins; Publications; Rattus; Reactive Oxygen Species; Reflex action; Reporting; Rodent; Rodent Model; Role; Sleep Apnea Syndromes; Sympathetic Nervous System; Testing; Therapeutic; Transcriptional Activation; Transferase; Trichostatin A; base; experience; experimental study; histone acetyltransferase; histone modification; hypoxia inducible factor 1; inhibitor/antagonist; innovation; insight; novel; prevent; protein H(3); transcription factor

Project Summary- Project 4 The overall goal of the Project 4 is to assess the epigenetic mechanisms underlying sympathetic activation caused by intermittent hypoxia (IH), a major manifestation of sleep apnea. Histone modification by lysine acetylation is a major epigenetic mechanism. Lysine acetylation is determined by equilibrium between histone acetyltransferases (HATs) and histone deacetylases (HDACs). Preliminary data showed that: a) IH inhibits HDAC activity with little or no effect on HAT activity, b) IH induces lysine acetylation of histone (H)-3, c) lysine acetylation is an early epigenetic mechanism initiated by IH, and d) Inhibiting HDAC activity results in HIF-1- stabilization and transcription. Based on the preliminary data, Project 4 tests the hypothesis that IH-evoked HIF-1 transcriptional activation requires lysine acetylation of the HIF-1α protein and histone-3, which in turn activates DNA methyl transferases leading to DNA methylation and long-lasting sympathetic activation. This hypothesis will be tested in rat pheochromocytoma (PC)-12 cell cultures, intact rats exposed IH, and in mice exhibiting spontaneous sleep apnea and uses molecular, biochemical and physiological approaches. Studies in Aim1 assess how IH inhibits HDAC activity. Experiments in Aim2 determine how decreased HDAC activity by IH activates HIF-1-mediated transcription. Aim 3 determines the consequences of HIF-1 activation by lysine acetylation on IH-evoked sympathetic activation. Aim 4 determines whether lysine acetylation by short-term IH leads to DNA methylation by long-term IH. Major conceptual and technical innovations of the Project 4 are: a) the hypothesis that lysine acetylation by short-term IH drives the long-term IH-induced DNA methylation is conceptually novel, and provides new mechanistic molecular insights into the progression of autonomic dysfunction in the context of sleep apnea from a reversible to a non-reversible phenotype, and b) assessing the significance of findings from experimental rodent model of IH in mice exhibiting natural sleep apnea. Project 4 has tight thematic linkages with Projects 1, 2, 3, and 4 and utilizes Core B facilities for exposing rodents and cell cultures to IH. Investigative team consists of molecular biologists, epigenesists, and physiologists who have long-standing experience and expertise with the proposed approaches and a track record of working together for number years as evidenced by joint publications. Successful completion of the Project 4 is anticipated to provide much needed molecular basis for progression of disease from a reversible to non-reversible phenotype, wherein currently no information is available.

项目摘要-项目4 项目4的总体目标是评估交感神经激活的表观遗传机制 由间歇性缺氧（IH）引起，这是睡眠呼吸暂停的主要表现。赖氨酸修饰组蛋白 乙酰化是主要的表观遗传机制。赖氨酸乙酰化是由组蛋白 乙酰转移酶（HAT）和组蛋白脱乙酰酶（HDAC）。初步数据显示：a）IH抑制 HDAC活性对HAT活性几乎没有影响或没有影响，B）IH诱导组蛋白（H）-3的赖氨酸乙酰化，c）赖氨酸 乙酰化是由IH启动的早期表观遗传机制，和d）抑制HDAC活性导致HIF-1-1表达。 稳定化和转录。基于初步的数据，项目4测试了假设， HIF-1转录激活需要HIF-1α蛋白和组蛋白-3的赖氨酸乙酰化， 激活DNA甲基转移酶，导致DNA甲基化和持久的交感神经激活。这 将在大鼠嗜铬细胞瘤（PC）-12细胞培养物、暴露于IH的完整大鼠和小鼠中检验假设 表现出自发性睡眠呼吸暂停，并使用分子、生物化学和生理学方法。研究 在Aim 1中评估IH如何抑制HDAC活性。Aim 2中的实验确定了HDAC活性的降低是如何 通过IH激活HIF-1介导的转录。目的3确定赖氨酸激活HIF-1的后果 乙酰化对IH诱发的交感神经激活的影响。目的4确定是否通过短期IH赖氨酸乙酰化 导致DNA甲基化。项目4的主要概念和技术创新是： 由短期IH引起的赖氨酸乙酰化驱动长期IH诱导的DNA甲基化的假设是 概念新颖，并提供了新的机制分子的见解自主的进展， 在睡眠呼吸暂停的情况下从可逆表型到不可逆表型的功能障碍，和B）评估 在表现出自然睡眠呼吸暂停的小鼠中，IH实验啮齿动物模型的发现的意义。 项目4与项目1、2、3和4有着紧密的主题联系，并利用核心B设施， 啮齿动物和细胞培养物到IH。调查小组由分子生物学家、表观遗传学家和 生理学家谁拥有长期的经验和专业知识与建议的方法和轨道 合作多年的记录，如联合出版物所证明。成功完成 预计项目4将为疾病从可逆性进展到非可逆性提供急需的分子基础。 不可逆表型，其中目前没有可用的信息。