Mechanisms Underlying Carotid Body-dependent Sympathetic Activation by Chronic Intermittent Hypoxia

慢性间歇性缺氧引起颈动脉体依赖性交感神经激活的机制

• 批准号: 10612094
• 负责人: Nanduri R Prabhakar
• 金额: $ 45.36万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10612094
• 关键词: Adenylate Cyclase; Affect; Autonomic Dysfunction; Biochemical; Biological; Biological Assay; Blood Pressure; Carotid Body; Cell membrane; Central Sleep Apnea; Chronic; Complex; Cyclic AMP; Data; Development; Exhibits; Exposure to; G-Protein-Coupled Receptors; Gases; Gene Deletion; Genetically Engineered Mouse; Glomus Cell; Goals; Hyperactivity; Hypoxia; Joints; Knockout Mice; Link; Mediating; Molecular; Mus; Nerve; Obstructive Sleep Apnea; Odorant Receptors; Patients; Peripheral; Persons; Physiological; Publications; Rattus; Receptor Activation; Receptor Signaling; Reflex action; Reporting; Research; Respiratory Disease; Rodent; Rodent Model; Role; Signal Transduction; Sleep Apnea Syndromes; Techniques; Testing; Therapeutic; comorbidity; conditional knockout; cyclic-nucleotide gated ion channels; experience; experimental study; innovation; interest; member; neuromechanism; novel; olfactory receptor; response; therapeutic evaluation

Project Summary- Project 1 Sleep apnea (SA) is a highly prevalent respiratory disease affecting several million people in the USA alone. Chronic Intermittent Hypoxia (CIH) is a hallmark manifestation of SA. Patients with SA, and rodents exposed to CIH exhibit elevated sympathetic nerve activity, which has been implicated in causing autonomic co- morbidities. The overall goal of the Project 1 is to delineate peripheral neural mechanisms underlying CIH- induced sympathetic activation and assess its impact on blood pressure. A heightened carotid body (CB) chemo reflex has been implicated as a major driver of CIH-induced sympathetic activation and gaseous messenger H2S mediates CB hyperactivity by CIH. Project 1 seeks to determine how H2S causes the CB activation by CIH. We test the hypothesis that H2S acting on olfactory receptor 78 (Olfr78) in glomus cells initiates a complex signaling cascade, involving a cAMP-dependent increase in [Ca2+]I leading to CB hyperactivity by CIH. We test this possibility using a combination of physiological, biochemical and molecular biological approaches on rats and mice exposed to CIH as well as in mice exhibiting spontaneous sleep apnea, and primary cultures of CB glomus cells. Studies in AIM 1 assess the role of Olfr78 in CB activation by CIH. AIM 2 determines whether CB activation by CIH requires cAMP activation by Olfr78 by H2S. AIM 3 determines how cAMP leads to CB activation by CIH. Experiments in AIM 4, determines the importance of CB H2S-Olfr78 signaling in CB excitation and sympathetic activation in mice exhibiting sleep apnea. Major conceptual and technical innovations include: a) H2S acting through odorant receptors mediates CIH-evoked CB excitation with profound consequences on autonomic functions is conceptually novel and has not been explored beyond the preliminary data presented in this application, b) assessing the significance of findings from experimental rodent model of CIH in mice exhibiting natural sleep apnea; and c) development of novel techniques to generate CB specific deletion of genes of interest. Project 1 has tight thematic linkages to Projects 2, 3, and 4 and utilizes Core B facilities for: a) exposing rats and mice to CIH, b) obtaining genetically engineered mice, c) targeted deletion of genes, and d) biochemical and molecular biological assays. Members of the investigative team have long-standing experience and expertise with the proposed approaches and a track record of working together as evidenced by joint publications. Successful completion of Project 1 is anticipated to establish a novel role for Olfr78 in mediating biological actions of H2S, which might lead to therapeutic strategies targeting of H2S-Olfr78 signaling to block CB reflex-dependent sympathetic hyperactivity.

项目摘要 - 项目1 睡眠呼吸暂停（SA）是一种高度普遍的呼吸道疾病，仅在美国就影响了数百万。 慢性间歇性缺氧（CIH）是SA的标志性表现。 SA和啮齿动物暴露的患者 CIH表现出较高的交感神经活动，这与引起自主神经共同 病态。项目1的总体目标是描述CIH-的外围神经机制 诱发交感神经激活并评估其对血压的影响。颈动脉体（CB）增强 化学反射已被认为是CIH引起的交感神经激活和气态的主要驱动力 Messenger H2S通过CIH介导CB的过度活动。项目1旨在确定H2S如何导致CB CIH激活。我们检验了H2S作用在glomus细胞中的嗅觉受体78（OLFR78）上的假设 启动复杂的信号级联 CIH多动症。我们结合生理，生化和分子来测试这种可能性 暴露于CIH的大鼠和小鼠以及表现自发睡眠的小鼠的生物学方法 呼吸暂停和CB肾小球细胞的一级培养。 AIM 1的研究评估OLFR78在CB激活中的作用 CIH。 AIM 2确定CIH激活是否需要H2S通过OLFR78的cAMP激活。目标3 确定CAMP如何导致CB激活CIH。 AIM 4中的实验确定了CB的重要性 在表现出睡眠呼吸暂停的小鼠中，CB激发和交感激活中的H2S-OLFR78信号传导。主要的 概念和技术创新包括：a）通过气味受体介导的cih诱发的H2S CB激发对自主功能产生深远的后果是概念上的，尚未 探索超出本应用程序中提供的初步数据，b）评估发现的重要性 从表现出自然睡眠呼吸暂停的小鼠中CIH的实验啮齿动物模型。 c）新颖的发展 产生CB特异性缺失的技术。项目1具有紧密的主题联系 项目2、3和4，并利用核心B设施的设施：a）将老鼠和小鼠暴露于CIH，b）遗传上获得 工程小鼠，c）靶向缺失基因，d）生化和分子生物学测定。成员 在调查团队中，有长期的经验和专业知识，并通过拟议的方法和 共同出版物证明了共同工作的记录。成功完成项目1是 预计将在介导H2s的生物学作用中确立OLFR78的新作用，这可能导致 靶向H2S-OLFR78信号传导的治疗策略，以阻止CB反射依赖性同情 多动症。