Circadian Effects in the Stroke Penumbra

脑卒中半影区的昼夜节律效应 几乎所有的啮齿动物中风研究都是在白天进行的。对于夜间啮齿动物，这是他们的非活动（非- 清醒）阶段。在人类中，更多的缺血性中风发生在白天，并且几乎所有的患者都在白天。 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） 相位我们假设这种“昼夜节律不匹配”导致了中风中的翻译问题。 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 活动期比非活动期中风更困难;（ii）活动期半暗带可能演变不同， 期与非活动期中风;和（iii）血管调节和细胞死亡机制可能受到影响 昼夜节律。从临床角度看，中风半暗带的两个重要方面是血液 血流和梗死进展。因此，我们将追求4个综合目标，以调查昼夜节律对流量的影响 和半影区的细胞死亡 在目标1中，我们将绘制半影血流、代谢、细胞反应、组织损伤和行为 结果在小鼠局灶性脑缺血在整个正弦周期的昼夜节律。在目标2中， 将绘制脑缺血对中风演变过程中中枢和外周昼夜节律的影响。在 目的3，我们检验昼夜节律基因Bmal 1调节内皮剪切应力的假设， 半暗带的血流动力学反应。在目标4中，我们检验了Bmal 1调节谷氨酸的假设 再摄取转运蛋白、抗氧化基因表达和抗凋亡介质是昼夜节律的基础 对兴奋性毒性、氧化应激和细胞凋亡的影响。 昼夜节律生物学影响生理学、疾病和对治疗的反应的几乎所有方面（Cederroth等人， Cell Metab 2019）。这个项目可能代表了重新评估的更大努力的第一步 实验中风和神经血管单位机制与“正确的”昼夜节律的背景。

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.