A Refined Murine Model of Post-sepsis Cognitive Impairment for Investigating Mitochondrial Abnormalities and Human ApoE4 Gene Polymorphisms

用于研究线粒体异常和人类 ApoE4 基因多态性的精制脓毒症后认知障碍小鼠模型

• 批准号: 10646579
• 负责人: Hiroshi Saito
• 金额: $ 22.23万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10646579
• 关键词: Acute; Age; Alzheimer' s Disease; Animal Model; Animals; Antibiotic Therapy; Antibiotics; Brain; Cecum; Cells; Chronic; Critical Illness; Defect; Delirium; Dementia; Disease susceptibility; Elderly; Enzymes; Exhibits; Functional disorder; Genes; Genetic Polymorphism; Genotype; Goals; Hospitals; Human; Impaired cognition; Incidence; Infection; Inflammation; Injections; Knock-in; Knock-in Mouse; Laboratory Animal Models; Life; Life Style; Ligation; Liquid substance; Long-Term Effects; Longitudinal Studies; Medical; Memory; Memory impairment; Mitochondria; Modeling; Mus; Muscle; Muscle Weakness; Mutant Strains Mice; Necrosis; Neurons; Operative Surgical Procedures; Pathology; Patients; Persons; Population; Predisposition; Prevention strategy; Procedures; Productivity; Protocols documentation; Public Health; Publishing; Quality of life; Recovery; Reporting; Research; Resuscitation; Risk Factors; Sepsis; Skeletal Muscle; Stains; Survivors; Swimming; Testing; Transmission Electron Microscopy; Wild Type Mouse; aged; apolipoprotein E-3; apolipoprotein E-4; brain tissue; cecal ligation puncture; clinically relevant; cognitive enhancement; cognitive testing; high risk; middle age; mitochondrial dysfunction; mortality; mouse model; novel; object recognition; prevent; skeletal muscle weakness; systemic inflammatory response; transcriptome sequencing; young adult

ABSTRACT Sepsis is an infection-initiated life-threatening medical condition accompanied by severe whole-body inflammation. Over 1.7 million sepsis survivors are now discharged from the hospital annually, and a majority of them report reduced quality of life due to considerable long-term dysfunction, called chronic critical illness, including muscle weakness and cognitive impairment after hospital discharge. We previously developed a clinically relevant murine sepsis-survivor model with an ICU-like resuscitation procedure that enables us to evaluate long-term muscle quality and function after recovery from sepsis. Our studies demonstrated that sepsis-survivor mice exhibit significant skeletal muscle weakness. Skeletal muscles from these sepsis-survivor mice also show profound mitochondrial structural and functional defects. In contrast to muscle dysfunction, little is known for cognitive dysfunction in sepsis survivors. Although there are several published studies using laboratory animal models for this issue, their results remain inconclusive due to several limitations; 1) cognitive impairment being assessed by stressful swimming maze tests which sepsis survivors perform poorly due to muscle weakness; 2) use of surgical sepsis models with artifactual necrosis and resulting systemic inflammation; and 3) the lack of antibiotics treatment and the lack of confirmation of sepsis recovery, thereby focusing on dysfunction “during sepsis” rather than “post-sepsis”, all limit current research. Importantly, all these limitations are resolved in our above-mentioned sepsis-survivor mouse model that confirms complete recovery from sepsis, allows sufficient duration (4 weeks or longer) after sepsis to study long term effects, and eliminates surgical procedures to avoid artifactual necrosis and inflammation. Thus, our well-refined sepsis- survivor mouse model for muscle weakness can potentially be an appropriate animal model to investigate post- sepsis long-term cognitive impairment. Our major hypothesis is that this sepsis-survivor model will exhibit long- term cognitive impairment. We also hypothesize that ApoE4 gene polymorphism, the most common AD- susceptible genotype, confers a higher risk of developing cognitive dysfunction after surviving sepsis. Additionally, we hypothesize that mitochondrial abnormalities are involved in such post-sepsis cognitive impairment. To test these hypotheses, two Specific Aims will be pursued. (1) To test whether wild type mice develop long-term cognitive impairment after sepsis; and (2) To test whether mutant mice carrying the human ApoE4 gene polymorphism have a higher risk of developing cognitive impairment after sepsis.

抽象的 败血症是通过严重的全身实现的感染引发的威胁生命的医疗状况 炎。现在，每年有超过170万个败血症存活率从医院出院，多数 其中报告称，由于长期功能障碍，称为慢性重症疾病，生活质量降低， 包括肌肉无力和出院后的认知障碍。我们以前开发了一个 具有ICU样复苏程序的临床相关的鼠败血症 - 幸存者模型，使我们能够 评估败血症恢复后的长期肌肉质量和功能。我们的研究表明 败血症的小鼠暴露了明显的骨骼肌无力。这些败血症活的骨骼肌肉 小鼠还显示出深远的线粒体结构和功能缺陷。与肌肉功能障碍相反， 在败血症存活中的认知功能障碍而闻名。尽管有几项已发表的研究使用 实验室动物模型对于此问题，由于几个局限性，其结果仍然尚无定论。 1）认知 通过压力大的游泳迷宫测试评估损害，由于 肌肉无力； 2）使用手术败血症模型与人为坏死和由此产生的全身性 炎; 3）缺乏抗生素治疗以及缺乏败血症的确认，从而 专注于功能障碍“在败血症期间”而不是“销售后”，所有这些都限制了当前的研究。重要的是，一切 这些局限性在我们上述败血症的小鼠模型中解决了，该模型确认了完整 从败血症中恢复，脓毒症后有足够的持续时间（4周或更长时间）来研究长期影响，并且 消除手术程序以避免人为坏死和炎症。那，我们精心设计的败血症 - 肌肉无力的幸存者小鼠模型可能是研究后研究的适当动物模型 败血症长期认知障碍。我们的主要假设是，该败血症 - 活节模型将显示长期 术语认知障碍。我们还假设APOE4基因多态性是最常见的AD- 易感基因型，承认败血症生存后患有认知功能障碍的风险更高。 此外，我们假设线粒体异常参与了这种后认知 损害。为了检验这些假设，将实现两个具体的目标。 （1）测试野生类型是否 败血症后，小鼠长期认知障碍； （2）测试突变小鼠是否 携带人APOE4基因多态性具有较高的认知障碍风险 败血症后。