Understanding pathology of sepsis-induced physical disability for future precision medicine.

了解脓毒症引起的身体残疾的病理学，以用于未来的精准医学。

• 批准号: 10713228
• 负责人: Robert T Mankowski
• 金额: $ 38.13万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10713228
• 关键词: Acute; Affect; Age; Animals; Atrophic; Biological; Biological Markers; Catabolism; Chronic; Chronically Ill; Clinical; Clinical Trials; Critical Illness; Development; Elderly; Ethnic Origin; Functional disorder; Future; Goals; Healthcare Systems; Heterogeneity; Hospitalization; Immune response; Immunologics; Immunosuppression; Impairment; Individual; Infection; Inflammation; Intervention; Laboratory Research; Life; Modeling; Muscle Weakness; Muscular Atrophy; Nutritional; Organ; Outcome; Pathology; Patients; Peripheral; Physical Function; Population; Principal Investigator; Quality of life; Race; Recovery; Risk; Role; Sepsis; Skeletal Muscle; Survivors; Syndrome; age effect; disability; dysbiosis; exercise training; functional decline; gut microbiome; human old age (65+); immunological status; improved; mode of exercise; mortality; muscle strength; patient population; personalized approach; physically handicapped; pre-clinical; precision medicine; prevent; profiles in patients; programs; septic patients; sex

ABSTRACT Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to an infection. Due to improved acute survival following sepsis, many patients develop chronic critical illness (CCI), defined as prolonged hospitalization with unresolved organ dysfunction. CCI frequently manifests as a persistent inflammation, immunosuppression, and catabolism syndrome (PICS). Sepsis survivors suffering from PICS have highly variable poor long-term outcomes, especially regarding muscle weakness, which manifests as atrophy, delays recovery, and leads to physical disability. Although we have demonstrated that sepsis leads to physical disability, which warrants interventions to prevent it, the majority of exercise training and nutritional clinical trials have been ineffective to prevent functional decline. A key deficiency of trials to date has been a “one size fits all” approach to intervention, ignoring any heterogeneity in patient populations (age, sex, and race/ethnicity). To develop precision medicine (or interventions), we need a better understanding of the contribution of age, sex, and race/ethnicity, and immunologically active peripheral organs to sepsis-induced physical disability. Part of this precision approach includes the gut microbiome. The gut microbiome uniquely affects host immune status, depends on biological variables, and interacts with and controls end-organ function such as skeletal muscle. Gut-microbiome dysbiosis is known to play a role in the overall pathology of sepsis and may be a driver of PICS and sepsis-induced acute and long-term muscle loss/weakness and physical disability. The Principal Investigator (PI) has demonstrated that older age is associated with worse clinical trajectories, long-term muscle-strength and physical-function outcomes, and has revealed that older adults have greater aberrations of the PICS biomarkers compared to younger individuals. The PI has also shown persistent gut-microbiome dysbiosis in sepsis patients and that gut microbiome differs between ages and sexes in a preclinical animal sepsis model. Given the current findings, the overarching goal for this application is to characterize the role of age, sex, race/ethnicity, and gut microbiome in the development of PICS leading to sepsis-induced muscle loss/weakness and physical disability. The goal of the PI laboratory’s research program over the next 5 years is to characterize (1) sepsis-induced chronic muscle loss/weakness and physical disability in sepsis survivors; (2) the role of PICS pathophysiology; (3) the effects of sex, age, and race/ethnicity on PICS and the development of physical disability; and (4) the unique contribution of the gut microbiome to heterogeneity of PICS and physical disability. Characterizing the heterogeneity of chronic sepsis-induced muscle loss/weakness and physical disability and creating patient profiles at risk of developing physical disability will be the key to applying precision medicine to prevent physical disability. Based on the findings of this study, future interventions can be customized to particular patients in terms of appropriate timing, type, and modality of exercise training and/or gut-function- enhancing treatments to prevent physical disability in an expanding population of chronically ill sepsis survivors.

抽象的 败血症是一种威胁生命的器官功能障碍，由宿主对感染的失调反应引起。由于 败血症后，急性生存改善，许多患者发生慢性疾病（CC​​I），定义为 长时间的住院治疗，无法解决器官功能障碍。 CCI经常表现为持久 炎症，免疫抑制和分解代谢综合征（图片）。败血症患有照片的生存 长期差的差异很大，尤其是关于肌肉无力的，这表现为萎缩， 延迟恢复，并导致身体残疾。尽管我们已经证明败血症会导致物理 残疾，需要进行干预措施，大多数运动培训和营养临床试验 无法防止功能下降。迄今为止，试验的关键缺陷是“一件尺寸适合所有人” 干预方法，忽略患者人群（年龄，性别和种族/种族）的任何异质性。到 开发精度医学（或干预措施），我们需要更好地了解年龄，性别，性别的贡献 以及种族/种族，以及具有败血症引起的身体残疾的免疫学活跃的外围器官。一部分 这种精度方法包括肠道微生物组。肠道微生物组独特地影响宿主免疫状态， 取决于生物学变量，并与骨骼肌等最终器官功能相互作用并控制。 已知肠道菌菌体营养不良症在败血症的整体病理中发挥作用，可能是图片的驱动力 败血症引起的急性和长期肌肉丧失/无力和身体残疾。首席研究员 （PI）已经证明，老年与临床轨迹较差，长期肌肉强度有关 和身体功能的结果，并揭示了老年人对图片有更大的畸变 与年轻人相比，生物标志物。 PI还显示了持续的肠道微生物组营养不良。 脓毒症患者和肠道微生物组在临床前动物败血症模型中的年龄和性别之间有所不同。 鉴于当前的发现，此应用程序的总体目标是表征年龄，性别的作用 种族/种族和肠道微生物组在开发导致败血症引起的肌肉损失/无力的图片中 和身体残疾。未来5年，PI实验室研究计划的目标是表征 （1）败血症诱发的慢性肌肉丧失/无力和败血症生存的身体残疾； （2）图片的作用 病理生理学； （3）性别，年龄和种族/种族对图片的影响和身体的发展 残疾； （4）肠道微生物组对图片和身体残疾的异质性的独特贡献。 表征慢性败血症引起的肌肉丧失/无力和身体残疾的异质性， 创建有生产残疾风险的患者概况将是将精确药物应用于 防止身体残疾。根据这项研究的发现，可以将未来干预措施定制为 特定的患者在适当的时机，类型和运动训练和/或肠道功能的方式方面 增强治疗方法，以防止长期败血症生存的人群不断扩大。