Characterization of an endogenous GABA-ergic mechanism underlying hypersomnia

睡眠过度的内源性 GABA 能机制的表征

• 批准号: 9128729
• 负责人: DAVID B RYE
• 金额: $ 59.45万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9128729
• 关键词: Adenosine; Adverse effects; Advocate; Affect; Amino Acids; Anesthesia procedures; Behavioral; Benzodiazepine Receptor; Benzodiazepines; Binding; Biological; Biological Markers; Biological Neural Networks; Brain; Bypass; Cerebrospinal Fluid; Circadian Rhythms; Clinic; Clinical; Complex; Consensus; Data; Development; Diagnostic; Diazepam Binding Inhibitor; Disabled Persons; Disease; Dose; Drug effect disorder; Engineering; Etiology; Exhibits; FDA approved; Flumazenil; Forensic Medicine; Functional disorder; Genetic; Goals; Head; Health; Health Professional; Human; Hypersomnias; Hypersomnolence; Impairment; In Vitro; Injection of therapeutic agent; Intravenous; Kleine-Levin Syndrome; Knowledge; Mediating; Medical; Morbidity - disease rate; Mus; Napping; Neurotransmitters; Obstructive Sleep Apnea; Outcome; Patients; Peptides; Pharmaceutical Preparations; Phase; Physiological; Physiology; Prostaglandins; Proteomics; Rattus; Reporting; Science; Sea; Sedation procedure; Signal Transduction; Site; Sleep; Specificity; Therapeutic; Time; Translating; Variant; Wakefulness; Wild Type Mouse; alertness; alternative treatment; clinical practice; cognitive task; cytokine; experience; gain of function; gamma-Aminobutyric Acid; heuristics; high throughput screening; hypnotic; improved; in vivo; insight; liquid chromatography mass spectrometry; loss of function; monoamine; mortality; novel; novel diagnostics; oleylamide; open label; patient population; positive allosteric modulator; psychostimulant; receptor; receptor function; relating to nervous system; sedative; socioeconomics; tool; vigilance

 DESCRIPTION (provided by applicant): Sleepiness that persists despite episodes of prolonged sleep (viz., hypersomnolence) negatively impacts morbidity and mortality. The sleep and circadian sciences have identified environmental, biological, and genetic factors that influence hypersomnolence, yet, little of this knowledge has been translated into the clinic. Valid and reliable means of assessment and biomarker(s) for hypersomnolence are lacking. Psychostimulants that enhance wake remain the default mainstays of treatment. Their efficacies depend on heightening the brain's excitatory monoamine signaling, but they can be ineffective and fraught with side effects. They are prescribed routinely which reinforces heuristic constructs that posit loss of function in the brain's wake- promoting networks as the principal arbiter of hypersomnolence. The alternative hypothesis - namely, that hypersomnolence reflects a gain in function in brain mechanisms subserving sleep - has its advocates. Naturally occurring putative somnogens that accumulate after restricting sleep include adenosine, prostaglandins, cytokines, the diazepam binding inhibitor (DBI), and oleamides, but none are proven to cause pathological sleepiness in humans. The knowledge gained has therefore not translated into rational, treatment alternatives for hypersomnolence. Human conditions in which hypersomnolence emerges sui generis, e.g., the `primary hypersomnias' (PH), afford a unique opportunity to derive novel mechanistic insights into `natural' sleep per se, because they bypass interpretative confounds of experimental paradigms that include sleep restriction. After excluding known causes of hypersomnolence in 32 PH patients, we have reported on an endogenous peptidergic bioactivity in their cerebrospinal fluids that mimics the actions of sedative-hypnotics and anesthesia. This physiology is reversible with benzodiazepine (BZD) antagonists in vitro, and translates in vivo to vigilance improvements that appear superior to conventional medications. Our major goal here is to advance mechanistic understanding of this putative sleep-inducing GABA-ergic bioactivity by determining its: 1) specificity to persistent and episodic hypersomnolence in PH and Kleine-Levin syndrome, respectively, vs. sleepiness associated with obstructive sleep apnea; 2) reliance upon the a-1 GABAA receptor subunit known to mediate sedation in vivo, and site of action relative to this receptor's BZD binding pocket through physiological interrogation of molecularly engineered receptor variants in vitro ; and 3) identity. These mechanistic details of pathological hypersomnolence promise to change medical practice by way of improved diagnostics and therapeutics.

 描述（由申请人提供）：尽管长时间睡眠，但嗜睡仍持续（即，嗜睡）对发病率和死亡率有负面影响。睡眠和昼夜节律科学已经确定了影响嗜睡的环境，生物和遗传因素，然而，这些知识很少被转化为临床。有效 缺乏可靠的评估方法和嗜睡的生物标志物。增强清醒的精神兴奋剂仍然是治疗的默认支柱。它们的功效取决于增强大脑的兴奋性单胺信号，但它们可能无效且充满副作用。它们是常规的处方，强化了启发式结构，即大脑唤醒促进网络功能的丧失，作为嗜睡的主要仲裁者。另一种假说--即嗜睡反映了大脑中有助于睡眠的机制的功能增强--也有其支持者。限制睡眠后自然产生的推定的睡眠原包括腺苷、肾上腺素、细胞因子、地西泮结合抑制剂（DBI）和油酰胺，但没有一种被证明会引起人类的病理性嗜睡。因此，所获得的知识尚未转化为嗜睡症的合理治疗替代方案。出现嗜睡的人类疾病，例如，“原发性睡眠过度”（PH）提供了一个独特机会，以获得对“自然”睡眠本身的新的机械见解，因为它们绕过了包括睡眠限制在内的实验范例的解释混乱。在排除了32例PH患者嗜睡的已知原因后，我们报告了他们脑脊液中的内源性肽能生物活性，模拟镇静催眠药和麻醉剂的作用。这种生理学是可逆的苯二氮卓类（BZD）拮抗剂在体外，并在体内转化为警惕性的改善，似乎上级传统的药物。我们的主要目标是通过确定其：1）分别对PH和Kleine-Levin综合征中持续性和发作性嗜睡的特异性，与阻塞性睡眠呼吸暂停相关的嗜睡相比，促进对这种假定的睡眠诱导GABA能生物活性的机制理解; 2）依赖于已知在体内介导镇静的α-lGABAA受体亚基，以及通过体外分子工程受体变体的生理询问相对于该受体的BZD结合口袋的作用位点;和3）身份。病理性嗜睡的这些机制细节有望通过改进诊断和治疗来改变医疗实践。