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

创伤性脑损伤是世界范围内与创伤相关的主要死亡和残疾原因。巨大的社会和经济影响要求更好地了解这一毁灭性的疾病。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亚型的诱导对包括中枢神经系统在内的不同器官系统具有保护作用。我们先前已经确定了HO-1在小胶质细胞对出血反应中的一个新的作用，即小胶质细胞HO-1的表达介导了血液的清除，但也产生了气体分子CO，后者反过来可以调节各种细胞通路。HO-1影响神经元损伤的确切分子机制尚不清楚。自身的初步数据表明，HO-1以CO依赖的方式调节小胶质细胞和其他胶质细胞的激活和极化。这些结果表明，炎症刺激(如HO-1控制的CO产生)引起的神经胶质细胞的反应性转化可能通过尚未确定的神经通路来调节患者的神经元损伤和功能障碍。一种这样的神经通路可能是控制昼夜节律的分子反馈环：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着的相关性。昼夜节律性不仅决定了睡眠-觉醒周期，而且几乎决定了每一种生理功能。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控蛋白组成，如周期2。它们活性的紊乱或不足会导致心血管和中枢神经系统疾病，而活性增加，特别是周期2的活性增加，已被证明具有保护作用。自己的人类数据表明，尤其是在第二阶段，在影响出血性或创伤性脑损伤后精神错乱、神经元结局和急性肾损伤的发生率方面发挥了作用。在昼夜节律自动调节反馈环和HO-1-CO酶系统之间存在着一个有趣的联系：“时钟基因”的转录活性被证明是CO依赖的。HO-1/CO系统确实可以影响出血性卒中后的昼夜节律性和神经元预后，并且其本身是以昼夜节律的方式调节的。目前，我们正在进一步探索这一重要而新颖的功能，该项目正在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创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性在这种毁灭性疾病中发挥中央保护性调节作用。

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.