CNS Pathways Integrating Respiratory and Metabolic Control

整合呼吸和代谢控制的中枢神经系统通路

• 批准号: 8686561
• 负责人: DONALD R. MC CRIMMON
• 金额: $ 59.09万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8686561
• 关键词: Achievement; Acids; Address; Affect; Alveolar; Amino Acids; Bilateral; Biology; Blood gas; Brain Stem; Breathing; Cell Nucleus; Cells; Data; Depressed mood; Development; Disease; Energy Metabolism; Environmental air flow; FOS gene; Future; Halorhodopsins; Homeostasis; Hormones; Human; Hypercapnic respiratory failure; Hypothalamic structure; Immunohistochemistry; In Vitro; Injection of therapeutic agent; Knowledge; Lateral; Leptin; Literature; Maintenance; Medial Dorsal Nucleus; Mediating; Medicine; Metabolic; Metabolic Control; Metabolism; Methods; Molecular; Mono-S; Motor Neurons; Mus; Nerve; Neural Pathways; Neuraxis; Neuromodulator; Neurons; Neurotransmitters; Obesity; Opsin; Pathway interactions; Patients; Peptides; Pharmacotherapy; Pontine structure; Population; Property; Resistance; Rhodopsin; Role; Structure of nucleus infundibularis hypothalami; Synapses; Syndrome; Technology; Testing; Time; To specify; Transgenic Mice; Viral; activity marker; base; clinically relevant; cytokine; energy balance; leptin receptor; novel; optogenetics; paraventricular nucleus; prevent; public health relevance; research study; respiratory; response; transmission process

DESCRIPTION (provided by applicant): Maintenance of arterial blood gas and acid-base homeostasis requires that a change in metabolism be matched by a proportional change in alveolar ventilation. Leptin, a cytokine hormone, has a central role in energy balance and has been implicated as an important contributor to the matching of ventilation to an aspect of metabolism in both mice and humans. This is clinically relevant as, for example, a subset of obese humans is resistant to leptin and hypoventilate with both an increase in arterial PCO2 and decrease in arterial PO2 (obesity hypoventilation syndrome, OHS). It is generally believed that leptin stimulates breathing through a CNS mechanism. However, multiple nuclei within the CNS contain leptin receptor expressing neurons (termed LepRb neurons) and there is almost no evidence as to which groups are involved in the stimulation of breathing. Based on preliminary studies and the literature we hypothesize that multiple specific groups of brainstem and hypothalamic LepRb neurons contribute to the respiratory stimulation. Additionally, peptide transmitters/modulators have been associated with many of these cell groups and pharmacologic manipulation of activity in these pathways could provide the basis for future development of clinically relevant pharmacological manipulation of activity in these pathways. Three Specific Aims will be addressed. In Aim 1, we will take advantage of Cre-loxP technology and optogenetic activation or silencing of specific LepRb neuronal groups in transgenic mice. Stimulation of breathing in response to selected activation of a specific LepRb neuronal group will suggest a role in breathing. Immunohistochemistry for the neuronal activity marker, c-Fos, will be used to identify cell groups that may participate as relay nuclei in pathways from specific LepRb neuronal groups to the CNS respiratory circuits. This potential role will be tested by using systemic leptin administration to stimulate breathing while determining whether bilateral inactivation of the target nucleus reduces the respiratory stimulation. In Aim 2, we will combine standard retrograde tracing with a novel transynaptic viral tracing method that crosses only 1 synapse to specify leptin-activated mono- and poly-synaptic pathways stimulating breathing. The peptide transmitters contained within these pathways will be identified immunohistochemically. In Aim 3, in vitro studies will define the impact of peptide transmitters within the leptin pathways on brainstem respiratory neurons and identify the cellular/molecular mechanisms underlying their influence. The combined studies will systematically identify CNS LepRb neuronal groups that stimulate breathing in response to systemic leptin administration. Additionally, paucisynaptic pathways mediating this influence will be revealed as will the identity of their peptide transmitters. Moreover, associated cellular/molecular mechanisms contributing to a stimulation of breathing will be defined. The findings could form the basis for the future development of pharmacotherapies for OHS patients.

描述（由申请人提供）：维持动脉血气和酸碱稳态，要求将代谢的变化与肺泡通气的比例变化相匹配。瘦素是一种细胞因子激素，在能量平衡中具有核心作用，并被牵涉到小鼠和人类中新陈代谢方面匹配与代谢方面相匹配的重要因素。这在临床上是相关的，因为例如，肥胖人类的一部分对瘦素具有抵抗力，并且剂量不足，而动脉PCO2的增加和动脉PO2的降低（肥胖症状不足综合症，OHS）。通常认为，瘦素通过CNS机制刺激呼吸。但是，中枢神经系统内的多个核包含表达神经元的瘦素受体（称为LEPRB神经元），几乎没有证据表明哪些组参与刺激呼吸的刺激。根据初步研究和文献，我们假设多个特定的脑干和下丘脑LEPRB神经元有助于呼吸刺激。此外，肽发射器/调节剂与许多细胞组有关，并且在这些途径中对活性的药物操纵可以为这些途径中活性的临床相关药理操作的未来发展提供基础。将解决三个具体目标。在AIM 1中，我们将利用转基因小鼠中特定的LEPRB神经元基团的Cre-LoxP技术以及光遗传学激活或沉默。响应特定LEPRB神经元组的选定激活而刺激呼吸将表明在呼吸中起作用。神经元活性标记C-FOS的免疫组织化学将用于识别可能从特定的特定途径中参与接力核参与的细胞组 LEPRB神经元组为CNS呼吸回路。该潜在作用将通过使用全身性瘦素给药来刺激呼吸，同时确定靶核的双侧失活是否会减少呼吸刺激。在AIM 2中，我们将将标准的逆行追踪与一种新型的透射病毒追踪方法相结合，该方法仅横穿1个突触以指定瘦素激活的单突触和多突触途径刺激呼吸。这些途径中包含的肽发射器将在免疫组织化学上鉴定出来。在AIM 3中，体外研究将定义瘦素途径中肽发射器对脑干呼吸神经元的影响，并确定其影响其影响的细胞/分子机制。合并的研究将系统地识别CNS LEPRB神经元基团，这些神经元基团响应全身性瘦素的给药刺激呼吸。此外，将揭示介导这种影响的Paucisynnaptic途径将被揭示 它们的肽发射器。此外，将定义导致呼吸刺激的相关细胞/分子机制。这些发现可能是OHS患者未来药物治疗的未来开发的基础。