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Torpor for cerebroprotection

麻木状态有利于脑保护

基本信息

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
项目类别：
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

项目摘要

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