Calcium homeostasis and cellular fitness in sepsis

脓毒症中的钙稳态和细胞适应性

基本信息

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
项目类别：
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

项目摘要

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 万美国人因败血症住院，然而，三分之一的幸存者死亡。高达 50% 的人会出现神经认知障碍，并且认知能力下降会持续长达 8 年。脓毒症住院占计划外再入院的比例高于心肌病住院脓毒症幸存者的五年死亡率超过了心力衰竭和慢性阻塞性肺病。这种持续性健康损失的机制仍有待确定。在脓毒症早期，线粒体被重组为一种适应性机制，以保护细胞免受任何影响未来的环境压力，例如复发性脓毒症，这些结构变化会给身体带来持久的改变。支持细胞表型所需的线粒体钙 (Ca2+) 稳态和代谢，对于多细胞生物体来说，这种现象的耐受性很差，并且是持续丧失健康的原因。我们的实验室花了近二十年的时间研究脓毒症，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 生成并保持细胞健康。我们已经证明，败血症后早期，线粒体去极化会产生 Ca2+ 信号。 Ca2+/钙调蛋白依赖性蛋白激酶 (CaMK) 家族转导这些 Ca2+ 信号并在串联介导线粒体裂变、线粒体自噬和氧化代谢的适应性变化，以减少最近，我们观察到脓毒症会重组线粒体钙单向转运蛋白。 (MCU) 复杂，对线粒体和细胞 Ca2+ 稳态产生持久的变化，我们认为，新陈代谢会扰乱整个有机体的细胞和组织功能。对败血症的“习得”反应，细胞重组 MCU 复合体以对抗 Ca2+ 的潜力未来损伤造成的超负荷；这会导致 Ca2+ 稳态、氧化的持久改变使用下呼吸道和腹膜内感染模型。相关的人类样本，我们提出以下目标：目标 1. 在小鼠和人类身上研究重组的 MCU 复合物如何改变 Ca2+ 稳态和氧化代谢，从而构成生物体的每个组织的表型。目标 2. 确定通过溶酶体和线粒体自噬和蛋白质降解的机制蛋白酶体是小鼠模型中 MICU1 表达持续缺失的根本原因败血症和人类败血症幸存者。这项新的实验工作将提供有关机制如何控制的基础知识脓毒症期间线粒体 Ca2+ 和代谢发生重组，导致细胞功能持续丧失导致健康逐渐丧失和生存缩短的表型。