Circadian Effects in the Stroke Penumbra

卒中半暗带的昼夜节律效应 几乎所有的啮齿动物中风研究都是在白天进行的。对于夜间活动的啮齿动物，这是它们不活动的(非 唤醒)阶段。在人类中，更多的缺血性中风发生在白天，几乎所有的患者 神经保护试验也在白天进行。但对于白天活动的人类来说，这是他们的活动(清醒) 相位。我们假设这种“昼夜节律不匹配”导致了中风的翻译问题。 我们的初步数据(一些发表在Esposito等人的《自然2020》上)表明：(I)神经保护可能是 活动期卒中较非活动期更困难；(Ii)活动期半暗带可能有不同的演变 相较于静止期卒中；(Iii)血管调节和细胞死亡机制可能受到影响 通过昼夜节律。从临床角度来看，中风半暗带的两个重要方面是血液。 血流和梗塞进展。因此，我们将追求四个综合目标来研究昼夜节律对流量的影响。 半影区的细胞死亡。 在目标1中，我们将绘制半暗带血流、新陈代谢、细胞反应、组织损伤和行为 小鼠局灶性脑缺血在整个昼夜节律正弦周期中的结果。在目标2中，我们 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图。在……里面 目的3，我们验证了昼夜节律基因BMal1调节内皮细胞剪切力的假设 半影区的血流动力学反应。在目标4中，我们检验了BMal1调节谷氨酸的假设 作为昼夜节律基础的重摄取转运体、抗氧化剂基因表达和抗凋亡介质 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到生理学、疾病和治疗反应的所有方面(Cederroth等人， Cell Metab 2019)。这个项目可能代表着重新评估的更大努力的第一步 具有“正确”昼夜节律背景的实验性中风和神经血管单位机制。

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.