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

氧化还原对代谢和线粒体生物能学的控制指导急性炎症和脓毒症的进程。

• 批准号: 9916767
• 负责人: Charles Emory McCall
• 金额: $ 38.75万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9916767
• 关键词: Acute; Address; Anabolism; Antioxidants; Bioenergetics; Cell Respiration; Cessation of life; Cysteine; Disease; Energy Supply; Equilibrium; Failure; Funding; Goals; Grant; Health; Health Care Costs; Homeostasis; Human; Immune; Immune system; Immunity; Infection; Inflammation; Knowledge; Metabolic; Metabolism; Mitochondria; Modeling; Molecular; National Institute of Allergy and Infectious Disease; National Institute of General Medical Sciences; Nuclear; Organ; Organ failure; Oxidation-Reduction; PDPK1 gene; Physiology; Proteins; Public Health; Reactive Oxygen Species; Recovery; Research; Resolution; Rogaine; SIRT1 gene; Sepsis; Sulfhydryl Compounds; Testing; Translational Research; United States National Institutes of Health; base; economic cost; global health; improved; monocyte; mortality; mouse model; prevent; programs; septic patients; systemic inflammatory response; targeted treatment; theories; therapeutic target

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.

概括 该MIRA提案与杰出PI的主要目标是多年不间断的NIH R01 急性炎症的资金和生产性研究是解决主要差距和未满足的需求 了解人类如何生存败血症，这是由高度致命的急性全身性炎症反应。 感染。大多数败血症死亡发生在器官期间，并因注射失调而免疫失败。不 基于分子的特异性疗法可用于这种健康困境。该建议将开发一个新的 并统一的败血症理论，根据该理论，持续的低能分解代谢状态，系统性 炎症惯性（SII），阻碍氧化代谢并防止免疫力失败和器官 从恢复恢复稳态所需的合成能量状态。从机械上讲，该提议的内容 工作模型认为，从促氧化剂合成代谢状态转换为持续的抗氧化分解代谢状态 基础Sii。进一步的理论是，钥匙上的功能性半胱氨酸基于甲醇的氧化还原“总机” 蛋白质稳态控制合成代谢和败血症期间的等效物 生物能力衰竭并促进高死亡率败血症。但是，关于SII是可逆的理论预测， 热靶向关键稳态可以恢复代谢平衡并实现免疫系统和器官 恢复并改善败血症生存。与可逆性概念一致，独立针对核 NAD+依赖性SIRT1和线粒体PDK1促进氧化还原和生物能平衡并增加 在败血症依赖性SII的小鼠模型中生存，原理证明发生在人类败血症中 单核细胞。 PI的资助的Nigms和Niaid R01在此MIRA中合并提供了早期的支持 对于败血症如何经常杀死的能量“供需差异”理论。合并PI 研究计划将最大程度地理解和针对性的公共卫生困境，以了解 我们仍然没有足够的了解，并且仍然是主要杀手。