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.

摘要 中风是美国成年人长期残疾的主要原因， 运动、感觉或认知功能中度至重度受损的幸存者，需要 专科护理尽管在卒中的急性（< 24小时）护理方面取得了进展，例如溶栓和 再通，中风患者仍然会经历脑损伤的进展，对患者造成负面影响。 结果。脑保护，即减轻对大脑整个神经血管单位的损伤，是一种 在中风护理研究中具有极高的优先级。昏睡是一种体温过低和新陈代谢不足的状态， 被认为是一种自我保护的状态我们已经确认了一个之前未被充分研究的， 在内侧核中表达κ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， POAKOR+神经元诱导了一种低体温和低代谢状态，我们称之为合成性麻痹。 初步数据表明，在实验性中风后立即诱导合成麻痹， 在中风后72小时，数据还表明， 合成性休眠改变核苷酸、脂质和柠檬酸循环的代谢，同时改变代谢产物 例如与中风后脑损伤进展相关的神经酰胺和琥珀酸盐。而 这些初步数据突出了几个关键的知识差距，将在拟议的 调查研究。首先，我们将研究中风后72小时观察到的脑保护作用是否 也改善长期行为结果（目标1）。第二，我们的初步数据表明， 合成麻痹的低温深度和持续时间可预测中风的大小，因此，我们将研究是否 脑卒中后合成麻痹的神经保护作用依赖或不依赖于低温 (Aim 2）。第三，虽然在合成休眠期间改变的代谢途径与那些改变的代谢途径重叠， 对于中风，尚不清楚这些代谢变化是否独立于体温过低而发生， 途径和代谢产物与抗肿瘤保护有关。我们将研究这些代谢变化， 识别响应合成性迟钝而发生独特改变的途径和代谢物， 描述森林保护的时空动态（目标3）。鉴别的代谢产物和代谢产物 这些途径可能是未来预防性干预措施的目标。圆满完成了 拟议的研究将表征合成torpor-mediated的机制基础， 保护和解决知识差距，是否诱导一个类似torpor-like状态， 特定神经回路的调节代表了治疗神经系统疾病的一种新的神经保护策略。 缺血性中风