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

摘要 Mira建议的主要目标来自一位拥有多年不间断的NIH R01的杰出PI 对急性炎症的资助和生产性研究是为了解决主要缺口和未得到满足的需求 了解人类如何在脓毒症中幸存下来，这种高度致命的急性全身炎症反应是由 感染。大多数败血症死亡发生在器官和免疫衰竭期间，这是由于调节失调的炎症造成的。不是 针对这一健康困境，有基于分子的特定疗法可用。这项提议将制定一项新的 和脓毒症的统一理论，根据该理论，持续的低能量分解代谢状态，全身 炎症惰性(SII)，阻碍氧化代谢，防止免疫力下降和器官 恢复体内平衡所需的合成代谢能量状态。从机械上讲，这项提议 工作模型假设，从促氧化剂合成代谢状态到持久抗氧化剂分解代谢状态的转换 这是SII的基础。它进一步推论，位于KEY上的一个基于半胱氨酸硫醇的功能性氧化还原“总机” 蛋白稳态控制着合成代谢和脓毒症期间的平衡，它的重新连接导致 生物能量学失败并导致高死亡率的脓毒症。然而，该理论预测SII是可逆的，并且 治疗靶向关键的稳态药物可以恢复新陈代谢平衡，并使免疫系统和器官 恢复和提高脓毒症的存活率。与可逆性概念一致，独立定位于核 NAD+依赖的SIRT1和线粒体PDK1促进氧化还原和生物能量平衡并增加 脓毒症依赖的SII小鼠模型的存活率，以及人类脓毒症血液中的原理证据 单核细胞。国际和平研究所资助的NIGMS和NIAID R01赠款合并在本Mira提供了早期支持 关于脓毒症如何经常致死的能源“供需不一致”理论。整合私募股权基金 研究计划将最大限度地了解并有针对性地治疗一个主要的公共卫生困境，关于 我们仍然缺乏足够的信息，这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.