Circadian effects in the stroke penumbra

中风半暗带的昼夜节律影响

• 批准号: 10444097
• 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/10444097
• 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; Ischemic Stroke; Knockout Mice; Knowledge; Link; Liver; MK801; Maps; Measures; Mediating; Mediator of activation protein; Metabolism; Mus; N-Methylaspartate; Nature; Neurologic; Neurological outcome; Neurons; Neuroprotective Agents; Oxidative Stress; Oxygen; Paper; Patient Recruitments; Patients; Pattern; Perfusion; Peripheral; Pharmacology; 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; Study Subject; Telemetry; Temperature; Terminology; Testing; Time; Up-Regulation; Vasodilation; Vibrissae; Western Blotting; antagonist; awake; behavioral outcome; 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; recruit; response; reuptake; sensor; shear stress; stroke patient; superoxide dismutase 1; time use; 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.

昼夜节律效果 几乎所有啮齿动物中风研究都是在白天进行的。对于夜间啮齿动物，这是他们的无活性（非 - 清醒）阶段。在人类中，白天发生更多的缺血性中风，几乎所有患者 神经保护试验也在白天招募。但是对于昼夜人来说，这是他们的活跃（醒着） 阶段。我们假设这种“昼夜节律不匹配”有助于翻译中风问题。 我们的初步数据（一些在Esposito等人，自然2020年发表）提出：（i）神经保护可能是 在主动相和非活动相中，更困难； （ii）阴影在活动中的演变可能有所不同 相对于非活动相冲程； （iii）血管调节和细胞死亡机制可能受到影响 由昼夜节律。从临床的角度来看，中风的两个重要方面是血液 流动和梗塞进展。因此，我们将追求4个综合目的来研究昼夜节律对流动的影响 和细胞死亡。 在AIM 1中，我们将绘制半流血，代谢，细胞反应，组织损伤和行为 昼夜节律整个正弦周期中小鼠局灶性脑缺血的结果。在AIM 2中，我们 将绘制脑缺血对中风进化过程中中央和周围昼夜节律的影响。 AIM 3，我们检验了昼夜节律BMAL1调节内皮剪切应力的假设 半阴茎的血液动力学反应。在AIM 4中，我们检验了BMAL1调节谷氨酸的假设 昼夜节律的重新摄取转运蛋白，抗氧化基因表达和抗凋亡介质 对兴奋性，氧化应激和凋亡的影响。 昼夜节律生物学几乎影响生理学，疾病和对疗法的反应的所有方面（Cederroth等， Cell Metab 2019）。该项目可能代表了重新评估应该更大的努力的第一步 具有“正确”昼夜节律的实验性中风和神经血管单位机制。