Integrated use of genomics, metabolomics, and cytokine profiling to validate the use of 'dirty' mice to study sepsis pathophysiology

综合使用基因组学、代谢组学和细胞因子分析来验证使用“脏”小鼠研究脓毒症病理生理学

• 批准号: 10257687
• 负责人: Thomas S Griffith
• 金额: --
• 依托单位: MINNEAPOLIS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-10-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10257687
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Address; Adult; Affect; American; Animal Model; Antigens; Biology; Biomedical Research; Birth; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Caring; Cells; Complement; Complex; Cues; Data; Event; Exposure to; Functional disorder; Genetic Transcription; Genomics; Goals; Health system; Hospital Costs; Hospitals; House mice; Housing; Human; Immune; Immune response; Immune system; Immunosuppression; Infection; Inflammatory; Intention; Intra-abdominal; Laboratory mice; Life; Malignant neoplasm of prostate; Medical; Metabolic; Microbe; Modeling; Molecular; Mus; Neonatal; Operative Surgical Procedures; Organ; Pathology; Patient Care; Patients; Physiological; Population; Positioning Attribute; Predisposition; Proteomics; Public Health; Publications; Recording of previous events; Reporting; Reproducibility; Research; Research Personnel; Resolution; Rodent; Rodent Model; Secondary to; Sepsis; Serum; Shapes; System; Testing; Training; Trauma Research; Vaccination; Veterans; Work; base; biological heterogeneity; cecal ligation puncture; chemokine; clinically relevant; cohort; commensal microbes; cost; cytokine; cytokine release syndrome; environmental change; experience; fitness; germ free condition; human model; macrophage; malignant breast neoplasm; metabolomics; microbial; monocyte; mortality; mouse model; neonate; neutrophil; novel; pathogenic microbe; polymicrobial sepsis; pre-clinical; readmission rates; response; secondary infection; septic; septic patients; tool; transcriptome sequencing; transcriptomics; validation studies

Each year ~2 million adult Americans develop sepsis and nearly 270,000 Americans die as a result of sepsis. In the U.S. VA health system in 2009, >35,000 Veterans were hospitalized with sepsis, and ~80% survived to hospital discharge (current numbers are likely higher). Veterans also have a high rate of hospital readmission following sepsis. Hospital costs associated with treating sepsis exceed $24B/year, making it the most expensive medical condition treated in the U.S. Faced with costly and burdensome patient care, it is imperative to better understand the pathophysiologic states experienced by these patients to deliver targeted care. Mice are one of the most important tools used in biomedical research, due in part to their ability to model complex physiological systems in humans. However, environmental microbial exposure is an important difference between basic human and laboratory mouse biology that must be considered when using mouse models to evaluate immune system fitness. Humans are naturally exposed to both commensal and pathogenic microbes daily from birth, and the immune system of adult humans has been trained and shaped by each microbe. In contrast, laboratory mice are often housed under specific pathogen-free (SPF) conditions. SPF housing has been instrumental in increasing experimental reproducibility, but it has simultaneously further distanced the mouse model from humans, largely because SPF mice live their lives with limited microbial exposure. Our proposal will leverage a novel mouse model that mimics critical aspects of the human immune system – where exposure to multiple ongoing and resolved infections is the norm. We will integrate transcriptomics, metabolomics, proteomics, and cytokine profiling to define the molecular basis of the pathophysiology and resolution of sepsis. The proposed validation studies will be key for supporting the use of microbially-experienced ‘dirty’ mice in sepsis research. There are no reported direct comparisons of immune responses in dirty septic mice to human patients. We posit that direct comparison of acute response in septic patients to sepsis models in dirty mice will show a closer correlation than the comparison between human and SPF mice. It has been argued that rodent models do not resemble the pathophysiology of human sepsis, an assumption boosted by studies claiming the molecular changes observed in human sepsis are different from the ones observed in rodents. Yet, the rodent system is an invaluable tool to advance current understanding of the immune system that will produce important information to understand septic pathology and provide clues for seeking ways to ameliorate the conditions. The main concern raised about dirty mice is the potential of increased variability in the commensal and pathogenic microbes they have encountered. If one intention of new mouse models for biomedical research is to better model humans with a diverse microbial experience, then using mice with a similarly diverse microbial exposure history must be viewed as a strength. It is important to emphasize dirty mice are meant to serve as a novel complement to, rather than replace, the SPF mice typically used in sepsis research. We see dirty mice as a valuable tool for discovering new efficacious sepsis therapies that may be sensitive to the environmental perturbations after microbial exposure.

每年约有 200 万美国成年人患败血症，近 27 万美国人死于败血症。 2009 年，在美国退伍军人事务部卫生系统中，超过 35,000 名退伍军人因败血症住院，约 80% 的人存活到 出院（目前的数字是可能的）退伍军人的再入院率也很高。 败血症后与治疗败血症相关的医院费用超过 $24B/年，成为最高的费用。 在美国治疗昂贵的医疗状况面对昂贵且繁重的患者护理，势在必行 更好地了解这些患者经历的病理生理状态，以提供有针对性的护理。 是生物医学研究中使用的最重要的工具之一，部分原因在于它们能够对复杂性进行建模 然而，环境微生物暴露是一个重要的区别。 使用小鼠模型进行实验时必须考虑基本人类生物学和实验室小鼠生物学之间的差异 评估免疫系统的适应性。人类自然会接触共生微生物和病原微生物。 从出生起，成年人的免疫系统就受到每种微生物的训练和塑造。 相比之下，实验室小鼠通常被饲养在特定的无病原体（SPF）条件下。 有助于提高实验的可重复性，但同时也进一步拉开了与实验的距离。 小鼠模型来自人类，很大程度上是因为 SPF 小鼠的生活中微生物接触有限。 该提案将利用一种模仿人类免疫系统关键方面的新型小鼠模型——其中 暴露于多种持续且已解决的感染是常态，我们将整合转录组学， 代谢组学、蛋白质组学和细胞因子分析来定义病理生理学的分子基础和 败血症的解决。 拟议的验证研究将是支持使用经历过微生物的“肮脏”小鼠的关键 脓毒症研究尚未报道肮脏脓毒症小鼠与人类免疫反应的直接比较。 我们假设将脓毒症患者的急性反应与肮脏小鼠的脓毒症模型进行直接比较。 有人认为，啮齿类动物与人类和 SPF 小鼠之间的比较显示出更密切的相关性。 模型与人类脓毒症的病理生理学并不相似，这一假设是由声称 在人类脓毒症中观察到的分子变化与在啮齿动物中观察到的分子变化不同。 系统是推进当前对免疫系统的理解的宝贵工具，该系统将产生 了解脓毒症病理学的重要信息，并为寻求改善脓毒症的方法提供线索 人们对肮脏小鼠的主要担忧是共生体变异性增加的可能性。 以及他们遇到的病原微生物。如果新的小鼠模型用于生物医学的话。 研究的目的是更好地模拟具有不同微生物经验的人类，然后使用具有类似微生物经验的小鼠 必须将多样化的微生物暴露史视为一种优势，重要的是要强调肮脏的老鼠。 目的是作为脓毒症研究中常用的 SPF 小鼠的新补充，而不是替代。 我们认为肮脏的小鼠是发现新的有效脓毒症疗法的宝贵工具，这些疗法可能对 微生物暴露后的环境扰动。