Nrf2-ARE信号通路抑制IL-1β诱导的程序性坏死在干预新生儿脓毒症后神经发育异常中的作用及其机制研究

新生儿脓毒症是新生儿期最常见的疾病之一，更是患儿远期罹患多种神经/精神疾病的高危因素。由于对其机制缺乏深入了解，目前尚无有效措施对高危人群进行救治。基于我国庞大的人口基数和潜在的生育高峰，新生儿脓毒症导致的神经发育异常已成为我国医疗卫生事业面临的重大难题之一。新生儿脓毒症后脑内持续增高的IL-1β，是造成患儿神经发育异常的关键因素。但具体的机制尚不明确。我们在前期研究中发现：分别通过直接抑制程序性坏死或激活Nrf2-ARE信号通路抑制炎症小体从而减少IL-1β产生，均可改善脓毒症新生大鼠神经发育。据此，我们提出假说：炎症小体在失去Nrf2-ARE信号通路抑制后的过度活化是新生儿脓毒症后IL-1β出现持续高表达的上游关键调控机制；程序性坏死是IL-1β造成神经元损伤的下游效应机制。通过证实此假说，既可以深入解析新生儿脓毒症后出现神经发育异常的分子机制，还可为临床干预提供新的策略和理论基础。

Neonatal sepsis is one of the most common diseases in newborns, which is also a well-known high-risk factor for impaired neurodevelopment. Due to the lack of in-depth understanding of its mechanism, currently there is no effective interventional measure for these high-risk population. Considering our huge population and the incoming burst in birth rate, the long-term neurological dysfunction caused by neonatal sepsis has become one of the major challenges for our health system. Persistent activation of IL-1β within the brain is the key factor for the impaired neurodevelopment. But the underlying mechanism is largely unknown. In our pilot study, we found that both directing inhibiting necroptosis or decreasing the production of IL-1β by activating Nrf2-ARE signal pathway, can rescue impaired neurodevelopment after neonatal sepsis. Therefore, we hypothesize that loss of inhibition from Nrf2-ARE signal pathway leads to activation of inflammasome which should be the major regulatory mechanism for massive production of IL-1β. While the necroptosis is the underlying executive mechanism for neuron injury. By validating our hypothesis with this research program, not only can we have a deep understanding of the pathogenesis of impaired neurodevelopment, but also could guide us to develop novel therapeutic strategy.