Redox control over metabolism and mitochondrial bioenergetics directs the course of acute inflammation and sepsis.

总结 这一MIRA提案的主要目标来自一位杰出的PI，多年来一直从事NIH R01研究。 急性炎症的资金和生产性研究是为了解决主要的差距和未满足的需求， 了解人类如何生存败血症，高度致命的急性全身炎症反应驱动的 感染大多数脓毒症死亡发生在炎症失调引起的器官和免疫衰竭期间。没有 基于分子的特异性疗法可用于这种健康困境。该提案将开发新的 脓毒症的统一理论，根据该理论，持续的低能量分解代谢状态，全身性 炎症惰性（SII），阻碍氧化代谢，防止免疫和器官衰竭 恢复体内平衡所需的合成代谢能量状态从机制上讲，这个提议 工作模型假定，从促氧化合成代谢状态到持续的抗氧化分解代谢状态的转换 是SII的基础。它进一步理论化，位于关键部位的功能性半胱氨酸硫醇基氧化还原“开关板” 蛋白质稳态控制着在败血症期间的平衡，它的重新连接导致 生物能量学失败并促进高死亡率败血症。然而，该理论预测SII是可逆的， 治疗靶向关键稳态可以恢复代谢平衡，使免疫系统和器官 恢复和改善脓毒症生存。根据可逆性概念，独立定向核武器 NAD+依赖性SIRT1和线粒体PDK1促进氧化还原和生物能量平衡， 在脓毒症依赖性SII小鼠模型中的存活率，以及在人脓毒症血液中发生的原理证明 单核细胞PI资助的NIGMS和NIAID R01赠款在此MIRA中合并提供了早期支持 能源“供需矛盾”理论，败血症如何经常死亡。整合PI 研究计划将最大限度地了解和有针对性的治疗一个主要的公共卫生困境， 我们对它的了解仍然不够，它仍然是一个主要的杀手。

SUMMARY The principal goal of this MIRA proposal from a distinguished PI with many years of uninterrupted NIH R01 funding and productive research in acute inflammation is to address the major gap and unmet need of understanding how humans survive sepsis, the highly lethal acute systemic inflammatory response driven by infection. Most sepsis deaths occur during organ and immune failure from dysregulated inflammation. No molecular-based specific therapies are available for this health dilemma. This proposal will develop a new and unifying theory of sepsis, according to which a persistent low-energy catabolic state, systemic inflammation inertia (SII), impedes oxidative metabolism and prevents failing immunity and organs from regaining the anabolic energy state needed to restore homeostasis. Mechanistically, this proposal's working model posits that a switch from a pro-oxidant anabolic state to a persistent antioxidant catabolic state underlies SII. It further theorizes that a functional cysteine thiol-based redox “switchboard” located on key protein homeostats controls the equilibrium between anabolism and during sepsis, and that its rewiring causes bioenergetics failure and promotes high mortality sepsis. However, the theory predicts that SII is reversible and therapeutically targeting key homeostats can restore metabolic balance and enable immune system and organ recovery and improve sepsis survival. Consistent with the reversibility concept, independently targeted nuclear NAD+ dependent SIRT1 and mitochondrial PDK1 promote redox and bioenergy equilibrium and increase survival in a mouse model of sepsis-dependent SII, and proof of principle occurs in human sepsis blood monocytes. The PI's funded NIGMS and NIAID R01 grants consolidated in this MIRA provided early support for the energy “supply-and-demand discrepancy” theory of how sepsis so often kills. Consolidating the PI's research program will maximize understanding and targeted treatment of a major public health dilemma, about which we are still insufficiently informed and which continues to be a major killer.