Sirt1 regulation of NFkB activation and inflammatory responses in sepsis

描述（由申请人提供）：脓毒性休克是一种全身炎症反应综合征，可导致多器官损伤和死亡。目前，对这种疾病没有有效的治疗方法。确定可以帮助控制脓毒症引起的炎症的新治疗靶点对于治疗这种毁灭性疾病至关重要。复杂炎症网络的激活是脓毒症中过度全身炎症反应的原因。NF-kB已被证明是脓毒症中调节这些炎症网络的中心参与者。然而，在脓毒症中NF-κ B活性的分子调控在很大程度上仍然是未知的。最近的研究表明，乙酰化是NF-κ B激活的一种新机制。据报道，Sirt 1，一种广泛表达于所有组织中的脱乙酰酶，在几种体外和体内系统中与NF-κ B相互作用并通过脱乙酰化抑制NF-κ B活性。然而，Sirt 1在脓毒症诱导的炎症反应中的功能和调节尚未研究。使用小鼠脓毒症模型，我们证明了Sirt 1通过调节NF-κ B乙酰化和激活来控制脓毒症期间的炎症反应。我们的初步数据表明，诱导脓毒症触发NF-kB乙酰化和激活的野生型小鼠，这是进一步增加Sirt 1基因敲除小鼠。有趣的是，Sirt 1激活白藜芦醇或Sirt 1基因传递抑制脓毒症诱导的NF-κ B乙酰化。此外，我们发现caspase激活导致Sirt 1降解，这可能是脓毒症中加重全身炎症的新途径。在本研究中，我们将验证Sirt 1在脓毒症中控制NF-κ B活化和炎症反应的假设。我们的具体目标是：（1）确定Sirt 1在脓毒症诱导的NF-κ B活化和全身炎症中的作用。我们将使用可诱导的Sirt 1基因敲除小鼠来评估Sirt 1在脓毒症诱导的全身性炎症中的作用;我们将检查caspase在脓毒症期间Sirt 1调节NF-κ B活化和炎症信号传导中的作用;（2）具体剖析Sirt 1在脓毒症期间内皮细胞炎症反应中对NF-κ B活化的控制。我们将定义Sirt 1控制脓毒症诱导的NF-κ B激活和内皮细胞炎症信号。我们将使用内皮特异性Sirt 1敲除小鼠来评估内皮Sirt 1在脓毒症中NF-κ B调节和炎症信号传导中的作用;（3）探索通过Sirt 1激活剂和Sirt 1基因递送调节NF-κ B活化在脓毒症诱导的炎症中的治疗潜力。我们将探索Sirt 1激活剂对脓毒症诱导的NF-kB激活和炎症信号传导的治疗潜力;我们将评估Sirt 1基因递送是否可以通过抑制NF-kB调节的炎症信号传导有效地保护脓毒症诱导的炎症。成功完成拟议的研究将揭示Sirt 1作为脓毒症诱导的NF-kB活化和炎症的新型调节剂，并验证Sirt 1作为治疗脓毒症相关炎症组织损伤的治疗靶点的潜力。

DESCRIPTION (provided by applicant): Septic shock is a systemic inflammatory response syndrome that causes multiple organ damage and death. Currently, there is no efficient treatment for the disease. Identifying novel therapeutic targets that can help control sepsis-induced inflammation is crucial to treat this devastating disease. Activation of complex inflammatory networks is responsible for the excessive systemic inflammatory response in sepsis. NF-kB has been demonstrated as a central player that regulates these inflammatory networks in sepsis. However, molecular regulation of NF-kB activity in sepsis remains largely unknown. Recent studies indicate that acetylation is a new mechanism in NF-kB activation. It has been reported that Sirt1, a deacetylase widely expressed in all tissues, interacts with NF-kB and inhibits NF-kB activity by deacetylation in several in vitro and in vivo systems. Yet, the function and regulation of Sirt1 in sepsis-induced inflammatory responses have not been studied. Using mouse models of sepsis, we demonstrate that Sirt1 controls inflammatory responses during sepsis by regulating NF-kB acetylation and activation. Our preliminary data showed that induction of sepsis triggered NF-kB acetylation and activation in wild type mice, which were further increased in Sirt1 knockout mice. Interestingly, Sirt1 activation by resveratrol or Sirt1 gene delivery inhibited sepsis-induced NF-kB acetylation. Furthermore, we showed that caspase activation resulted in Sirt1 degradation, which may function as a new pathway to aggravate systemic inflammation in sepsis. In the proposed studies, we will test the hypothesis that Sirt1 controls NF-k B activation and inflammatory responses during sepsis. Our specific aims are: (1) to define the role of Sirt1 in sepsis-induced NF-kB activation and systemic inflammation. We will use inducible Sirt1 knockout mice to assess the role of Sirt1 in sepsis-induced systemic inflammation; we will examine the role of caspase in Sirt1 regulation of NF-kB activation and inflammatory signaling during sepsis; (2) to specifically dissect Sirt1 control of NF-kB activation in endothelial cell inflammatory responses during sepsis. We will define Sirt1 control of sepsis-induced NF-kB activation and inflammatory signaling in endothelial cells. We will use endothelial-specific Sirt1 knockout mice to assess the role of endothelial Sirt1 in NF-kB modulation and inflammatory signaling in sepsis; (3) to explore the therapeutic potential of modulating NF-kB activation by Sirt1 activators and Sirt1 gene delivery in sepsis-induced inflammation. We will explore the therapeutic potential of Sirt1 activators on sepsis-induced NF-kB activation and inflammatory signaling; we will evaluate whether Sirt1 gene delivery can effectively protect against sepsis-induced inflammation by inhibiting NF-kB-regulated inflammatory signaling. Successful completion of the proposed studies will disclose Sirt1 as a novel modulator of sepsis-induced NF-kB activation and inflammation, and validate the potential of Sirt1 as a therapeutic target to treat sepsis-associated inflammatory tissue damage.