Circadian Effects in the Stroke Penumbra

中风半暗带的昼夜节律影响

• 批准号: 10576931
• 负责人: Eng H. Lo
• 金额: $ 50.24万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10576931
• 关键词: ARNTL gene; Affect; Animal Housing; Antioxidants; Apoptosis; Apoptotic; Astrocytes; Autoradiography; Bioinformatics; Blood Vessels; Blood flow; Blood specimen; Brain; CCL2 gene; Cell Death; Cells; Cerebral Ischemia; Circadian Rhythms; Clinical; Clinical Trials; Cyclic AMP; Data; Disease; Endothelium; Epinephrine; Etiology; Evolution; Failure; Female; Gene Expression; Genes; Glucose; Glutamates; Heart; Hemostatic function; Histopathology; Human; Hydrocortisone; Hypercapnia; In Vitro; Infarction; Ischemia; Ischemic Stroke; Knockout Mice; Knowledge; Link; Liver; MK801; Maps; Measures; Mediating; Mediator; Metabolism; Mus; N-Methylaspartate; Nature; Neurologic; Neurological outcome; Neurons; Neuroprotective Agents; Oxidative Stress; Oxygen; Paper; Patient Recruitments; Patients; Pattern; Perfusion; Peripheral; Phase; Physiology; Plasminogen Activator Inhibitor 1; Proteins; Publishing; Rattus; Reactive Oxygen Species; Regulation; Research; Rodent; Rodent Model; Role; Signal Transduction; Sleep; Small Interfering RNA; Stroke; Telemetry; Temperature; Terminology; Testing; Time; Up-Regulation; Vasodilation; Vibrissae; Western Blotting; antagonist; awake; behavioral outcome; candidate identification; circadian; circadian biology; circadian regulation; deprivation; excitotoxicity; experimental study; gain of function; hemodynamics; in vivo; ischemic injury; lead candidate; loss of function; male; neuroprotection; neurovascular unit; novel; optical imaging; pharmacologic; recruit; response; reuptake; sensor; shear stress; stroke patient; superoxide dismutase 1; tissue injury; tool; treatment response

Circadian Effects in the Stroke Penumbra Almost all rodent stroke research is performed in the daytime. For nocturnal rodents, this is their inactive (non- awake) phase. In humans, more ischemic strokes occur during the daytime, and almost all patients in neuroprotection trials are also recruited in the daytime. But for diurnal humans, this is their active (awake) phase. We hypothesize that this “circadian mismatch” contributes to translational problems in stroke. Our preliminary data (some published in Esposito et al, Nature 2020) suggest that: (i) neuroprotection may be more difficult in active phase versus inactive phase stroke; (ii) the penumbra may evolve differently in active phase versus inactive phase stroke; and (iii) vascular regulation and cell death mechanisms may be affected by circadian rhythm. From a clinical perspective, the two important aspects of the stroke penumbra are blood flow and infarct progression. Therefore, we will pursue 4 integrated aims to investigate circadian effects on flow and cell death in the penumbra. In Aim 1, we will map penumbral blood flow, metabolism, cellular response, tissue injury and behavioral outcomes in mouse focal cerebral ischemia across the entire sinusoidal cycle of circadian rhythm. In Aim 2, we will map the effects of cerebral ischemia on central and peripheral circadian rhythms during stroke evolution. In Aim 3, we test the hypothesis that the circadian gene Bmal1 regulates endothelial shear stress that underlies hemodynamic response in the penumbra. In Aim 4, we test the hypothesis that Bmal1 regulates glutamate reuptake transporters, antioxidant gene expression, and anti-apoptotic mediators that underlie circadian influences on excitotoxicity, oxidative stress and apoptosis. Circadian biology affects almost all aspects of physiology, disease, and response to therapies (Cederroth et al, Cell Metab 2019). This project may represent the first step in what should be a larger effort to re-assess experimental stroke and neurovascular unit mechanisms with the “correct” circadian context.

中风半暗带的昼夜节律影响 几乎所有啮齿类动物中风研究都是在白天进行的，对于夜间活动的啮齿类动物来说，这是它们的不活动（非活动）。 在人类中，更多的缺血性中风发生在白天，并且几乎所有患者都处于白天。 神经保护试验也在白天进行，但对于白天活动的人来说，这是他们的活跃（清醒）。 我们发现这种“昼夜节律不匹配”会导致中风的转化问题。 我们的初步数据（一些发表在 Esposito 等人，Nature 2020）表明：（i）神经保护可能是 活动期中风与非活动期中风相比更困难；(ii) 活动期半影的演变可能不同； 阶段与非活动期中风；以及（iii）血管调节和细胞死亡机制可能受到影响 从临床角度来看，中风半暗带的两个重要方面是血液。 因此，我们将追求 4 个综合目标来研究昼夜节律对血流的影响。 和半影中的细胞死亡。 在目标 1 中，我们将绘制半影血流、新陈代谢、细胞反应、组织损伤和行为 在目标 2 中，我们研究了小鼠局灶性脑缺血在整个昼夜节律正弦周期中的结果。 将绘制中风演变过程中脑缺血对中枢和外周昼夜节律的影响。 目标 3，我们检验昼夜节律基因 Bmal1 调节内皮剪切应力的假设 在目标 4 中，我们测试了 Bmal1 调节谷氨酸的假设。 再摄取转运蛋白、抗氧化基因表达和昼夜节律基础的抗凋亡介质 对兴奋性毒性、氧化应激和细胞凋亡的影响。 昼夜节律生物学几乎影响生理学、疾病和治疗反应的所有方面（Cederroth 等， Cell Metab 2019）。该项目可能代表了重新评估更大努力的第一步。 具有“正确”昼夜节律背景的实验性中风和神经血管单元机制。