Torpor for cerebroprotection

麻木状态有利于脑保护

• 批准号: 10716469
• 负责人: Eric C Landsness
• 金额: $ 49.5万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10716469
• 关键词: Acute; Address; Adult; Biology; Body Temperature; Brain; Brain Injuries; Caring; Ceramides; Citric Acid Cycle; Clinical Trials; Clozapine; Data; Development; Event; Future; Genetic; Goals; Hibernation; Hour; Impairment; Infarction; Injury; Intervention; Investigation; Ischemia; Ischemic Stroke; Knowledge; Lipids; Measures; Medial; Mediating; Metabolic; Metabolic Pathway; Metabolic stress; Metabolism; Middle Cerebral Artery Occlusion; Modeling; Motor; Mus; Neurons; Outcome; Oxides; Pathway interactions; Patient-Focused Outcomes; Patients; Physiological; Population; Pre-Clinical Model; Preoptic Areas; Reporting; Research; Role; Sensory; Stress; Stroke; Succinates; Testing; Therapeutic; United States; behavior test; behavioral outcome; cerebroprotection; cognitive function; disability; experience; improved; kappa opioid receptors; medical specialties; metabolic rate; metabolomics; mortality; natural hypothermia; negative affect; neural circuit; neurovascular unit; novel; nucleotide metabolism; post stroke; prevent; research study; response; stroke patient; stroke survivor; thrombolysis; tool; translational study; treatment strategy; Acute; Address; Adult; Biology; Body Temperature; Brain; Brain Injuries; Caring; Ceramides; Citric Acid Cycle; Clinical Trials; Clozapine; Data; Development; Event; Future; Genetic; Goals; Hibernation; Hour; Impairment; Infarction; Injury; Intervention; Investigation; Ischemia; Ischemic Stroke; Knowledge; Lipids; Measures; Medial; Mediating; Metabolic; Metabolic Pathway; Metabolic stress; Metabolism; Middle Cerebral Artery Occlusion; Modeling; Motor; Mus; Neurons; Outcome; Oxides; Pathway interactions; Patient-Focused Outcomes; Patients; Physiological; Population; Pre-Clinical Model; Preoptic Areas; Reporting; Research; Role; Sensory; Stress; Stroke; Succinates; Testing; Therapeutic; United States; behavior test; behavioral outcome; cerebroprotection; cognitive function; disability; experience; improved; kappa opioid receptors; medical specialties; metabolic rate; metabolomics; mortality; natural hypothermia; negative affect; neural circuit; neurovascular unit; novel; nucleotide metabolism; post stroke; prevent; research study; response; stroke patient; stroke survivor; thrombolysis; tool; translational study; treatment strategy

ABSTRACT Stroke is the leading cause of long-term disability among adults in the United States, with half of all stroke survivors experiencing moderate to severe impairment in motor, sensory, or cognitive function that require specialty care. Despite advances in the acute (< 24 hour) care of stroke, such as thrombolysis and recanalization, stroke patients still experience progression of brain injury that negatively affects patient outcomes. Cerebroprotection, the mitigation of damage to the entire neurovascular unit of the brain, is an extremely high priority in stroke care research. Torpor, a state of hypothermia and hypometabolism, has long been hypothesized to represent a cerebroprotective state. We have identified a previously under-studied, conserved population of GABAergic neurons expressing the kappa opioid receptor (KOR) in the medial preoptic area (POA) termed POAKOR+. In preliminary studies, we found that chemogenetic activation of POAKOR+ neurons induced a hypothermic and hypometabolic state that we refer to as synthetic torpor. Preliminary data suggest that induction of synthetic torpor immediately after experimental stroke reduces infarct size and decreases mortality in mice at 72 hours post-stroke. The data also suggest that induction of synthetic torpor alters metabolism of nucleotides, lipids, and the citric acid cycle, while altering metabolites such as ceramides and succinate that are associated with the progression of brain injury after stroke. While promising, these preliminary data highlight several key knowledge gaps that will be addressed in the proposed research study. First, we will investigate whether the cerebroprotective effects observed 72 hours after stroke also improve long-term behavioral outcomes (Aim 1). Second, our preliminary data suggests that the hypothermic depth and duration of synthetic torpor predicts stroke size, thus, we will investigate whether the cerebroprotective effects of synthetic torpor following stroke are dependent or independent of hypothermia (Aim 2). Third, while the metabolic pathways that are altered during synthetic torpor overlap with those altered by stroke, it is unknown if these metabolic changes occur independently of hypothermia and if the altered pathways and metabolites are related to cerebroprotection. We will investigate these metabolic changes, identify the pathways and metabolites that are uniquely altered in response to synthetic torpor, and characterize the temporal-spatial dynamics of cerebroprotection (Aim 3). Identified metabolites and metabolic pathways may represent targets for future cerebroprotective interventions. Succesful completion of the proposed research study will characterize the mechanistic underpinnings underlying synthetic torpor-mediated cerebroprotection and address the knowledge gap on whether induction of a torpor-like state through modulation of specific neural circuits represents a novel cerebroprotective strategy for the treatment of ischemic stroke.

抽象的 中风是美国成年人长期残疾的主要原因，其中一半的中风 在运动，感觉或认知功能中遇到中等至重度损害的幸存者需要 专业护理。尽管在急性（<24小时）的中风护理方面取得了进步，例如溶栓和 重新定性，中风患者仍然经历脑损伤的进展，对患者产生负面影响 结果。脑保护是减轻对大脑整个神经血管单元损害的损害，是 中风护理研究的优先级极为高。 Torpor是体温过低和低代谢状态，长期以来 假设代表脑保护状态。我们已经确定了先前研究不足的人， 保守的GABA能神经元中表达Kappa阿片受体（KO）的群体 peroptic区域（POA）称为po+。在初步研究中，我们发现 po+神经元诱导了我们称为合成torpor的体温过低和低代谢状态。 初步数据表明，实验中风后立即诱导合成Torpor降低 势力72小时后，梗塞大小并降低小鼠的死亡率。数据还表明诱导 合成Torpor改变核苷酸，脂质和柠檬酸周期的代谢，同时改变代谢物 例如，与中风后脑损伤进展有关的神经酰胺和琥珀酸酯。尽管 这些初步数据很有希望，突出了几个关键知识差距 研究。首先，我们将研究中风后72小时观察到脑保护作用是否观察到 还可以改善长期行为结果（AIM 1）。第二，我们的初步数据表明 合成Torpor的低温深度和持续时间可以预测中风的大小，因此，我们将研究是否是否研究 中风后合成圆环的脑保护作用取决于或独立于体温过低 （目标2）。第三，而在合成圆环中改变的代谢途径与那些改变的代谢途径重叠 通过中风，未知这些代谢变化是否独立于体温过低，并且是否改变了 途径和代谢产物与脑食保护有关。我们将研究这些代谢变化， 识别响应于合成torpor的途径和代谢产物，并 表征脑保护的时间空间动力学（AIM 3）。确定的代谢物和代谢 途径可能代表未来脑保护干预措施的目标。成功完成 拟议的研究将表征合成Torpor介导的基础机械基础 脑保护并解决有关是否通过诱导torpor状态的知识差距 特定神经回路的调节代表了一种治疗的新型脑保护策略 缺血性中风。