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 脓毒症是一种由感染引起的危及生命的疾病，伴有严重的全身症状 现在每年有超过 170 万脓毒症幸存者出院，其中大多数患者已出院。 其中一些人报告称，由于严重的长期功能障碍（称为慢性危重病），生活质量下降， 包括出院后的肌肉无力和认知障碍。 临床相关的小鼠脓毒症幸存者模型，具有类似 ICU 的复苏程序，使我们能够 评估脓毒症康复后的长期肌肉质量和功能。 脓毒症幸存者小鼠表现出明显的骨骼肌无力。 与肌肉功能障碍相比，小鼠还表现出严重的线粒体结构和功能缺陷。 尽管有几项已发表的研究使用了脓毒症幸存者的认知功能障碍，但人们对它知之甚少。 对于这个问题的实验动物模型，由于一些局限性，他们的结果仍然没有定论：1）认知； 通过压力游泳迷宫测试评估损伤，脓毒症幸存者由于以下原因表现不佳 肌肉无力；2) 使用具有人为性坏死的手术脓毒症模型并导致全身性坏死 炎症；3) 缺乏抗生素治疗且缺乏脓毒症康复的确认，从而 重点关注“脓毒症期间”而不是“脓毒症后”的功能障碍，所有这些都限制了当前的研究。 这些局限性在我们上述的脓毒症幸存者小鼠模型中得到了解决，该模型证实了完整的 从脓毒症中恢复，允许脓毒症后有足够的时间（4周或更长时间）来研究长期影响，以及 消除了外科手术以避免人为坏死和炎症，因此，我们精心设计的败血症- 肌肉无力的幸存者模型可能是研究后遗症的合适动物模型 我们的主要假设是，这种脓毒症幸存者模型将表现出长期认知障碍。 我们还追踪了 ApoE4 基因多态性，这是最常见的 AD- 易感基因型，在脓毒症幸存后出现认知功能障碍的风险更高。 此外，我们认为线粒体异常与脓毒症后认知能力有关 为了检验这些假设，将追求两个具体目标（1）检验是否为野生型。 小鼠在败血症后出现长期认知障碍；以及（2）测试突变小鼠是否 携带人类ApoE4基因多态性的人患认知障碍的风险较高 败血症后。