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

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，占所有中风患者的一半 运动、感觉或认知功能中度至重度受损的幸存者，需要 特殊护理。尽管在中风的急性（< 24小时）护理方面取得了进展，例如溶栓和 血管再通，中风患者仍然会经历脑损伤的进展，对患者产生负面影响 结果。脑保护，即减轻大脑整个神经血管单位的损伤，是一种 中风护理研究中具有极高的优先权。麻木是一种体温过低和代谢减退的状态，长期以来 被假设代表一种脑保护状态。我们已经确定了一个以前未被充分研究的， 内侧表达 kappa 阿片受体 (KOR) 的 GABA 能神经元的保守群体 视前区 (POA) 称为 POAKOR+。在初步研究中，我们发现化学遗传学激活 POAKOR+ 神经元诱导体温过低和代谢低下的状态，我们称之为合成麻木状态。 初步数据表明，实验性中风后立即诱导合成麻木可减少 小鼠中风后 72 小时的梗死面积并降低死亡率。数据还表明，诱导 合成休眠改变核苷酸、脂质和柠檬酸循环的代谢，同时改变代谢物 例如与中风后脑损伤进展相关的神经酰胺和琥珀酸盐。尽管 这些初步数据很有希望，突出了几个关键的知识差距，这些差距将在拟议的 研究性学习。首先，我们将研究中风后72小时是否观察到脑保护作用 还可以改善长期行为结果（目标 1）。其次，我们的初步数据表明 低温深度和合成麻木的持续时间可以预测中风的大小，因此，我们将研究是否 中风后合成麻木的脑保护作用取决于或独立于体温过低 （目标 2）。第三，虽然在合成麻木期间改变的代谢途径与那些改变的代谢途径重叠 由于中风，目前尚不清楚这些代谢变化是否独立于体温过低而发生，以及这些代谢变化是否会改变 途径和代谢物与脑保护有关。我们将研究这些代谢变化， 识别响应合成麻木而独特改变的途径和代谢物，以及 表征脑保护的时空动态（目标 3）。已鉴定的代谢物和代谢 途径可能代表未来脑保护干预的目标。顺利完成了 拟议的研究将描述合成麻木介导的机制基础 脑保护并解决关于是否通过诱导类似麻木状态的知识差距 特定神经回路的调节代表了一种新的脑保护策略，用于治疗 缺血性中风。