Characterizing the role of myeloid-specific heme oxygenase-1 (HO-1) in the regulation of circadian rhythmicity, neuroinflammation and neuronal injury following brain trauma

表征骨髓特异性血红素加氧酶-1 (HO-1) 在脑外伤后昼夜节律、神经炎症和神经元损伤调节中的作用

• 批准号: 398425865
• 负责人: Professor Dr. Dieter-Henrik Heiland
• 金额: --
• 依托单位: Klinik für Anästhesiologie und Intensivmedizin
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/398425865?language=en
• 关键词: Characterizing; role; myeloid; specific; heme

Traumatic brain injury (TBI) is the leading cause of death and disability related to trauma worldwide. The high social and economic impact calls for a better understanding of this devastating disease. The heme oxygenase (HO) enzyme degrades heme to biliverdin, iron and carbon monoxide (CO). Induction of HO-1 isoform constitutes protection in different organ systems including the central nervous system. We have previously identified a novel role for HO-1 in microglia in response to hemorrhage in that microglial HO-1 expression mediates clearance of blood but also produces the gaseous molecule CO that in turn can regulate various cellular pathways. The exact molecular mechanisms of how HO-1 influences neuronal injury remain to be elucidated. Own preliminary data suggest that HO-1 regulates the activation and polarization of both microglia and other glia cells in a CO-dependent manner. These results suggest that reactive transformation of glial cells due to inflammatory stimuli such as HO-1-controlled CO production may modulate neuronal damage and functional impairment in patients via neuronal pathways yet to be determined. One such neuronal pathway could be the molecular feedback loop controlling circadian rhythmicity: There is a striking correlation between neuronal injury following stroke or trauma and the organism’s internal circadian rhythm. Circadian rhythmicity not only determines sleep-wake cycles but nearly every physiological function. On a molecular basis, it is generated by a family of “clock genes”, consisting of several transcription factors and regulatory proteins such as Period 2. Disturbance or deficiency in their activity leads to cardiovascular and central nervous system disease, while increased activity especially of Period 2 has been shown to be protective. Own human data suggest a role especially for Period 2 in influencing the incidence of delirium, neuronal outcome and acute kidney injury following hemorrhagic or traumatic brain injury. An interesting link has been shown to exist between the circadian auto-regulatory feedback loop and the HO-1-CO enzyme system: transcriptional activity of "clock genes" has been shown to be CO-dependent. The HO-1/CO system can indeed influence circadian rhythmicity and neuronal outcome after hemorrhagic stroke and is itself regulated in a circadian manner. Currently, we are further exploring this important and novel function in a project deciphering the crosstalk between central and peripheral circadian rhythmicity following organ injury. In this novel proposed project, we would like to extent our knowledge of the mechanisms related to injury after brain trauma and how the HO-1/CO enzyme system, via regulation of circadian rhythmicity, serves as a central protective regulator in this devastating disease.

创伤性脑损伤（TBI）是世界范围内与创伤相关的死亡和残疾的主要原因。这种严重的社会和经济影响要求人们更好地了解这种毁灭性疾病。血红素加氧酶（HO）将血红素降解为胆绿素、铁和一氧化碳（CO）。HO-1亚型的诱导在包括中枢神经系统在内的不同器官系统中构成保护。我们以前已经确定了HO-1在小胶质细胞中响应出血的新作用，即小胶质细胞HO-1表达介导血液的清除，但也产生气体分子CO，进而可以调节各种细胞途径。HO-1如何影响神经元损伤的确切分子机制仍有待阐明。自己的初步数据表明，HO-1调节激活和极化的小胶质细胞和其他胶质细胞在CO依赖性的方式。这些结果表明，反应性转化的神经胶质细胞由于炎症刺激，如HO-1控制的CO生产可能会调节神经元损伤和功能障碍的患者通过神经元通路尚未确定。一个这样的神经元通路可能是控制昼夜节律的分子反馈回路：中风或创伤后的神经元损伤与生物体的内部昼夜节律之间存在显著的相关性。昼夜节律不仅决定了睡眠-觉醒周期，而且几乎决定了所有的生理功能。在分子基础上，它是由一个“时钟基因”家族产生的，由几个转录因子和调节蛋白组成，如周期2。其活动的紊乱或缺乏导致心血管和中枢神经系统疾病，而活动增加，特别是第2阶段的活动增加已被证明是保护性的。自身的人体数据表明，尤其是在第2阶段，在影响出血性或创伤性脑损伤后谵妄、神经元结局和急性肾损伤的发生率方面具有作用。一个有趣的联系已被证明存在于昼夜自动调节反馈回路和HO-1-CO酶系统之间：“时钟基因”的转录活性已被证明是CO依赖性的。HO-1/CO系统确实可以影响出血性卒中后的昼夜节律和神经元结局，并且其本身以昼夜节律的方式进行调节。目前，我们正在进一步探索这一重要而新颖的功能，在一个项目中破译器官损伤后中枢和外周昼夜节律之间的串扰。在这个新提出的项目中，我们希望扩大我们对脑外伤后损伤相关机制的了解，以及HO-1/CO酶系统如何通过调节昼夜节律，在这种毁灭性疾病中作为中央保护调节器。