Calcium homeostasis and cellular fitness in sepsis

脓毒症中的钙稳态和细胞适应性

• 批准号: 10892600
• 负责人: MATTHEW Randall ROSENGART
• 金额: $ 56.29万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10892600
• 关键词: Acute; American; Animals; Anxiety; Biological; Biological Response Modifier Therapy; Biology; Brain; Ca(2+)-Calmodulin Dependent Protein Kinase; Calcium; Calcium Signaling; Caring; Cell Respiration; Cell Survival; Cell physiology; Cells; Cessation of life; Chronic Disease; Chronic Obstructive Pulmonary Disease; Complex; Cytoprotection; Development; Equilibrium; Exhibits; Family member; Functional Magnetic Resonance Imaging; Future; Generations; Health; Heart; Heart failure; Hippocampus; Homeostasis; Hospitalization; Hospitals; Human; Immune; Impaired cognition; Infection; Inflammatory; Kidney; Knowledge; Learning; Life; Link; Liver; Lower respiratory tract structure; Lysosomes; Mediating; Membrane Potentials; Mental disorders; Messenger RNA; Metabolism; Mitochondria; Modeling; Mus; Myocardial Infarction; Organism; Pathway interactions; Patients; Phenotype; Production; Recovery; Recurrence; Sampling; Sepsis; Stress; Stroke; Structure; Survivors; Tissues; Trauma; Work; calcium uniporter; cell injury; cytokine; diagnostic tool; experience; fear memory; fitness; healing; hospital readmission; improved; in vivo; innovation; intraperitoneal; mitochondrial membrane; mortality; mouse model; multicatalytic endopeptidase complex; neurocognitive disorder; novel; preservation; protein degradation; psychologic; response; septic patients; stoichiometry; systemic inflammatory response; uptake; vasogenic edema

ABSTRACT Two million Americans are hospitalized for sepsis each year, and 1 in 3 die. Those that survive, however, are not cured. Neurocognitive disorders occur in up to 50%, and cognitive decline continues for up to 8 years. Sepsis hospitalizations account for a higher proportion of unplanned readmissions than those for myocardial infarction, heart failure, and COPD. Five-year mortality for sepsis survivors exceeds that for heart failure and stroke. The mechanisms underlying this persistent loss of health remain to be defined. We hypothesize that early during sepsis the mitochondrion is restructured as an adaptive mechanism to protect the cell against any future environmental stress, such as recurrent sepsis. These structural changes impart lasting alterations to the mitochondrial calcium (Ca2+) homeostasis and metabolism necessary to support a cellular phenotype, which for a multicellular organism are poorly tolerated and underlie a persistent loss of health. Our lab has spent nearly two decades studying sepsis to elucidate the Ca2+-dependent mechanisms that regulate mitochondrial biology to balance Ca2+ homeostasis and ATP generation and preserve cellular health. We have shown that early after sepsis, mitochondrial depolarization generates a Ca2+ signal. Members of the family of Ca2+ /calmodulin-dependent protein kinases (CaMK) transduce these Ca2+ signals and work in tandem to mediate adaptive changes in mitochondrial fission, mitophagy, and oxidative metabolism to lessen cellular damage. More recently, we observed that sepsis restructures the mitochondrial calcium uniporter (MCU) complex, imposing long-lasting changes to mitochondrial and cellular Ca2+ homeostasis and metabolism that perturb cellular and tissue function across the entire organism. We propose that as a ‘learned’ response to sepsis, the cell restructures the MCU complex to counter the potential for Ca2+ overload with future insult; this imparts long-lasting alterations in Ca2+ homeostasis, oxidative metabolism, and tissue phenotype. Using models of lower-respiratory tract and intraperitoneal infection and correlative human samples, we propose the following aims: Aim 1. To study in mice and humans how a restructured MCU complex alters Ca2+ homeostasis and oxidative metabolism and thereby, the phenotype of each tissue comprising the organism. Aim 2. To define the mechanisms of mitophagy and protein degradation through the lysosome and proteasome as underlying causes of the persistent loss of MICU1 expression in murine models of sepsis and in human sepsis survivors. This new experimental work will provide foundational knowledge as to how the mechanisms governing mitochondrial Ca2+ and metabolism are restructured during sepsis to underlie a persistent loss of cellular phenotype that leads to a progressive loss of health and shortened survival.

抽象的 每年有200万美国人因败血症而住院，三分之一的死亡。但是，那些生存的人 没有治愈。神经认知障碍的发生在多达50％的情况下，认知能力下降长达8年。 败血症住院时间比心肌占据计划外的再入院率更高 梗塞，心力衰竭和COPD。败血症生存的五年死亡率超过了心力衰竭和 中风。这种持续性健康丧失的机制仍有待定义。我们假设这一点 败血症的早期，线粒体被恢复为一种自适应机制，以保护细胞免受任何 未来的环境压力，例如复发性败血症。这些结构性变化赋予了持久的改变 线粒体钙（CA2+）稳态和代谢，以支持细胞表型， 对于多细胞生物而言，它的耐受性不佳，是健康持续丧失的基础。 我们的实验室花了近二十年的时间研究败血症，以阐明Ca2+依赖性机制 调节线粒体生物学以平衡Ca2+稳态和ATP生成并保留细胞健康。 我们已经表明，败血症后，线粒体沉积会产生Ca2+信号。成员 Ca2+ /钙调蛋白依赖性蛋白激酶（CAMK）的家族翻译这些CA2+信号，并在 串联介导线粒体裂变，线粒体和氧化代谢的自适应变化以减少 细胞损伤。最近，我们观察到败血症修复了线粒体钙统一 （MCU）复合物，对线粒体和细胞CA2+稳态施加持久的变化 整个生物体中扰动细胞和组织功能的代谢。我们建议 “学会”对败血症的反应，细胞修复MCU复合物以应对Ca2+的潜力 超负荷未来的侮辱；这会在Ca2+体内稳态，氧化中持续变化。 代谢和组织表型。使用低呼吸道和腹膜内感染的模型以及 相关的人类样本，我们提出以下目的： 目的1。在小鼠和人类中学习恢复的MCU复合物如何改变Ca2+稳态和 氧化代谢，从而是每个组织完成生物体的表型。 目标2。定义通过溶酶体和蛋白质降解的机制 蛋白酶体是在鼠模型中的持续性MICU表达持续丧失的根本原因 败血症和人类败血症生存。 这项新的实验工作将提供有关如何管理机制的基本知识 线粒体Ca2+和代谢在败血症期间恢复，以持续损失细胞 表型导致健康逐渐丧失并缩短生存。