Development of a Novel Animal Model for Spinal Cord Injury with Sepsis

脓毒症脊髓损伤新型动物模型的开发

• 批准号: 10665862
• 负责人: Samirkumar Patel
• 金额: $ 22.91万
• 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: 2023-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10665862
• 关键词: Abdomen; Acute; Address; Affect; Animal Model; Animals; Antibiotics; Biochemical; Blood; Cause of Death; Clinical; Complication; Contusions; Development; Diagnosis; Functional disorder; Goals; Histologic; Histology; Histopathology; Hospitalization; Impairment; Individual; Indwelling Catheter; Infection; Inflammatory; Injections; Injury; Left; Length of Stay; Lesion; Life; Life Expectancy; Liquid substance; Locomotor Recovery; Medical; Mitochondria; Modeling; Molecular; Multiple Trauma; Muscle; Muscle Weakness; Outcome Measure; Phase; Physiological; Population; Predisposing Factor; Predisposition; Procedures; Quality of life; Rattus; Recovery; Recovery of Function; Research Personnel; Research Proposals; Resuscitation; Rodent; Rodent Model; Secondary to; Sensory; Sepsis; Severities; Spinal; Spinal Cord; Spinal cord injury; Spinal cord injury patients; Spleen; Sports; Survival Rate; Survivors; Testing; Therapeutic; Time; Tissues; Trauma; Vertebral column; Violence; body system; catheter associated UTI; clinically relevant; cytokine; decubitus ulcer; design; falls; functional outcomes; gray matter; improved; inflammatory marker; innovation; microbial; model development; mortality; motor recovery; multidisciplinary; novel; skeletal muscle weakness; success; vehicular accident; white matter; young adult

Summary Abstract Sepsis is a predominant life-threatening secondary complication following traumatic spinal cord injury (SCI). Several predisposing factors such as polytrauma, prolonged/repeated hospital stay, pressure ulcer, and indwelling catheters make SCI patients more susceptible to microbial infections that can lead to sepsis. Sepsis is a leading cause of death after spinal trauma and is associated with poor functional outcomes among survivors. Depending on the time of onset, there are two sepsis types. Sepsis diagnosed within 48hr of initial injury is termed “primary” sepsis, and when its onset occurs after 48hr, it is known as “secondary” sepsis. Though sepsis with SCI is a serious condition leading to diminished life expectancy and quality of life, this combined medical issue has not been well studied. This is mainly due to lack of an appropriate animal model. Accordingly, the goal of proposed study is to develop and validate a novel clinically relevant rodent model that closely mimics the long- term dysfunction of survivors of sepsis after SCI. This model will be validated with six parameters: 1) survival rate, 2) infection severity, 3) inflammatory cytokines, 4) locomotor score, 5) muscle force and 6) histopathology. Our team has developed a clinically relevant rodent sepsis model consisting of polymicrobial abdominal sepsis by cecal slurry (CS) injection followed by a delayed but repeated ICU-like resuscitation procedure with fluids and antibiotics; this refined model allows us to investigate long-term physical dysfunction among sepsis survivors. Our main approach is to combine this long-term sepsis survivor model with rat spinal contusion model to mimic either “primary” (Aim 1) or “secondary” (Aim 2) sepsis after SCI. Our central hypothesis is that the cumulative effects of sepsis plus SCI will impair spontaneous motor recovery, limit spinal cord tissue sparing, exacerbate skeletal muscle weakness, and increase mortality. Two specific Aims are designed to test this hypothesis. In Aim 1, we will induce sepsis immediately after SCI to mimic “primary” sepsis by CS injection followed by ICU- like resuscitation initiated at 8 hrs. To mimic “secondary” sepsis, in Aim 2, we will induce sepsis at 6 weeks after SCI by CS injection and resuscitation initiated at 8hrs after sepsis induction. SCI animals in Aim 1 will undergo weekly locomotor testing for 6 weeks and in Aim 2, for a total of 12 weeks (6 weeks before sepsis induction and 6 weeks after) to assess spontaneous recovery. After final locomotor assessments, survivors will be subjected to ex vivo muscle force testing, histological examination, and mitochondrial function analyses to assess muscle weakness. Spinal cord tissue will be used for quantitative histology of spared gray and white matter as well as lesion volume that will be correlated with locomotor recovery. Successful development of this model will allow us to investigate detailed molecular/physiological mechanisms of sepsis following SCI, with a long-term goal of developing therapeutic strategies to improve quality of life in the afflicted population. Success of this project is assured by our strong multi-disciplinary team including Drs. Patel (MPI, SCI researcher), Saito (MPI, sepsis researcher), Butterfield (Co-I, muscle researcher) and Stromberg (Co-I, biostatistician).

摘要 摘要 脓毒症是创伤性脊髓损伤（SCI）后主要危及生命的继发并发症。 多种诱发因素，如多发伤、长期/反复住院、压疮和 留置导管使 SCI 患者更容易受到微生物感染，从而导致败血症。败血症 是脊柱创伤后死亡的主要原因，并且与幸存者功能不良结果相关。 根据发病时间，脓毒症可分为两种类型。初次受伤后 48 小时内诊断出脓毒症的是 称为“原发性”脓毒症，48小时后发病则称为“继发性”脓毒症。虽然败血症 SCI 是一种严重的疾病，会导致预期寿命和生活质量下降，这种综合医疗 问题还没有得到很好的研究。这主要是由于缺乏合适的动物模型。据此，目标 拟议研究的目的是开发和验证一种新型的临床相关啮齿动物模型，该模型密切模仿长期 SCI 后败血症幸存者的足月功能障碍。该模型将通过六个参数进行验证：1）生存 率，2）感染严重程度，3）炎症细胞因子，4）运动评分，5）肌肉力量和6）组织病理学。 我们的团队开发了一种临床相关的啮齿动物败血症模型，包括多种微生物腹部败血症 通过盲肠浆 (CS) 注射，然后进行延迟但重复的类似 ICU 的复苏程序，使用液体和 抗生素；这个完善的模型使我们能够调查脓毒症幸存者的长期身体功能障碍。 我们的主要方法是将这种长期脓毒症幸存者模型与大鼠脊髓挫伤模型相结合来模拟 SCI 后“原发性”（目标 1）或“继发性”（目标 2）败血症。我们的中心假设是累积 脓毒症加 SCI 的影响将损害自发运动恢复、限制脊髓组织保留、加剧 骨骼肌无力，增加死亡率。设计了两个具体目标来检验这一假设。在 目标 1，我们将在 SCI 后立即诱导脓毒症，通过注射 CS 模拟“原发性”脓毒症，然后进入 ICU- 就像8小时开始的复苏一样。为了模拟“继发性”败血症，在目标 2 中，我们将在术后 6 周诱发败血症。 脓毒症诱导后 8 小时开始通过 CS 注射和复苏进行 SCI。目标 1 中的 SCI 动物将接受 每周进行运动测试，持续 6 周，在目标 2 中，总共 12 周（脓毒症诱导前 6 周， 6周后）评估自然恢复。最终运动评估后，幸存者将接受 离体肌肉力量测试、组织学检查和线粒体功能分析来评估肌肉 弱点。脊髓组织将用于幸存的灰质和白质以及 与运动恢复相关的病变体积。该模型的成功开发将允许 我们研究 SCI 后脓毒症的详细分子/生理机制，长期目标是 制定治疗策略以改善受影响人群的生活质量。这个项目的成功在于 我们强大的多学科团队（包括博士）保证了这一点。 Patel（MPI、SCI 研究员）、Saito（MPI、脓毒症 研究员）、巴特菲尔德（Co-I，肌肉研究员）和 Stromberg（Co-I，生物统计学家）。