Integrative Consequences of Intermittent Hypoxia

间歇性缺氧的综合后果

• 批准号: 10409549
• 负责人: Nanduri R Prabhakar
• 金额: $ 250.34万
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10409549
• 关键词: Address; Adhesions; Adult; Affect; Air; Autonomic Dysfunction; Biochemical; Blood; Cardiovascular Diseases; Cardiovascular Manifestation; Carotid Body; Cell Culture Techniques; Cells; Central Sleep Apnea; Chronic; Clinical; Collaborations; Disease; Endothelial Cells; Epigenetic Process; Exhibits; Experimental Models; Exposure to; Funding; Gene Expression; Genes; Goals; Hyperactivity; Hypertension; Hypoxia; Investigation; Knowledge; Lead; Leukocytes; Measurement; Mediating; Modeling; Molecular; Morbidity - disease rate; Mus; Nerve; Neuraxis; Obstructive Sleep Apnea; Organ; Pathologic; Pathology; Patients; Peripheral; Persons; Physiological; Program Research Project Grants; Recovery; Reflex action; Research; Research Personnel; Respiratory Disease; Risk Factors; Rodent; Rodent Model; Role; Sensory; Sensory Receptors; Signal Transduction; Sleep Apnea Syndromes; Stimulus; Sum; Sympathetic Nervous System; System; Technology; United States National Institutes of Health; clinically relevant; comorbidity; genetic approach; genome-wide; inflammatory marker; innovation; insight; mouse model; neuromechanism; neurophysiology; novel; novel therapeutic intervention; programs; relating to nervous system; response

Project Summary- Overall This application is for a new Program Project Grant entitled "Integrative consequences of intermittent hypoxia”. Chronic intermittent Hypoxia (CIH) is a hall mark manifestation of sleep apnea, a highly prevalent respiratory disease affecting several million people in the USA alone. Patients with sleep apnea and rodents exposed to IH exhibit hyperactive sympathetic nervous system, which has been implicated in many of the pathologies caused by sleep apnea. The overarching goal of the proposed Program is to determine how CIH leads to sympathetic nerve activation and determine its consequences. Specific Aims of the program are: AIM 1- Determines the neural mechanism(s) contributing to sympathetic nerve activation by IH. Peripheral and central neural mechanisms associated with sympathetic activation by CIH which will be determined in Projects 1 and 2. AIM 2- Consequences of sympathetic activation by CIH, which will be addressed in Project 3 by determining the contribution of sympathetic activation to endothelial cell activation by CIH. AIM 3- Elucidates the epigenetic mechanisms underlying CIH-induced sympathetic nerve activation, which will be the focus of Project 4. All four Projects will be supported by an Administrative Core and a Scientific Core. Studies in this program utilize rodents exposed to an IH paradigm mimicking the blood O2 saturation profiles akin to those occurring during sleep apnea as well as in mice exhibiting natural sleep apnea. Conceptual innovation- Cellular and molecular mechanisms underlying the sympathetic activation by CIH proposed in this program are novel, which in addition to sleep apnea may also be applicable to other cardiorespiratory diseases. Major technical innovation includes assessing the significance of findings from experimental rodent model of IH in a naturally occurring sleep apnea mouse model. Investigators in this program have demonstrated expertise at the cellular, molecular, and systems levels of investigation and have strong record of collaborations. Completion of the program is anticipated to provide important insights for developing novel therapeutic strategies for alleviating autonomic co-morbidities associated with IH, which is a major manifestation of sleep apnea. Because of the tight thematic linkages across the projects, the total knowledge gained from the overall program will truly be greater than the sum derived from each project.

项目摘要总体 此应用程序是针对名为“间歇性缺氧的综合后果”的新计划项目赠款。 慢性间歇性缺氧（CIH）是睡眠呼吸暂停的大厅标记表现，这是一种高度普遍的呼吸 仅在美国就影响了数百万人。睡眠呼吸暂停和啮齿动物的患者 IH暴露的多动交感神经系统，在许多病理中都暗示了这一点 由睡眠呼吸暂停引起。拟议程序的总体目标是确定CIH如何导致 交感神经激活并确定其后果。该计划的具体目的是：目标1- 确定促成IH交感神经激活的神经机制。外围和中央 与CIH的同情激活相关的神经机制将在项目1和 2。目标2- CIH同情激活的后果，该项目将通过确定在项目3中解决 交感神经激活对CIH的内皮细胞激活的贡献。瞄准3-阐明表观遗传学 CIH引起的交感神经激活的机制，这将是项目4的重点。 项目将得到行政核心和科学核心的支持。该计划的研究使用 暴露于IH范式的啮齿动物模仿类似于在 睡眠呼吸暂停以及表现出自然睡眠呼吸暂停的小鼠。概念创新 - 细胞和分子 该程序中提出的CIH激活同情激活的机制是新颖的，这在 除睡眠呼吸暂停外，还可能适用于其他心肺疾病。主要的技术创新 包括评估IH实验啮齿动物模型中发现的重要性 睡眠呼吸暂停鼠标模型。该计划中的研究人员在细胞中表明了专业知识， 分子和系统的投资水平，并具有强大的合作记录。完成 预计计划将提供重要的见解，以制定新的治疗策略来减轻 与IH相关的自主神经症，这是睡眠呼吸暂停的主要表现。因为 整个项目之间的紧密主题联系，从整个计划中获得的总知识将真正是 大于每个项目得出的总和。