Reversal of Immunoparalysis Following Traumatic Brain Injury and Systemic Hemorrhage in a Juvenile Rat Model

幼年大鼠模型中创伤性脑损伤和全身出血后免疫麻痹的逆转

• 批准号: 10449830
• 负责人: Eric Anthony Sribnick
• 金额: $ 18.76万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-15 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10449830
• 关键词: Acute; Adolescent; Adrenergic beta-Antagonists; Affect; Animal Model; Animals; Anti-Cholinergics; Anti-Inflammatory Agents; Area; Attenuated; Blood; Brain; Brain Injuries; Caring; Cause of Death; Cells; Child; Childhood; Childhood Injury; Chronic; Clinical; Clinical Trials; Cognition; Cognitive; Complication; Critical Illness; Data; Denervation; Development; Elements; Enrollment; Foundations; Funding; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Hemorrhage; Human; Hypovolemia; IL7 gene; Immune; Immune Targeting; Immunohistochemistry; Immunologic Adjuvants; Immunologics; Immunology; Immunophenotyping; Immunosuppression; Impaired cognition; Impairment; Incidence; Infection; Inflammation; Inflammatory Response; Injury; Interferons; K-Series Research Career Programs; Lead; Leukocytes; Life; Mediating; Medical; Memantine; Mentors; Methods; Modeling; Morbidity - disease rate; Multiple Trauma; Nerve; Nervous System Trauma; Neuraxis; Neurocognitive; Neurological outcome; Nicotinic Receptors; Nosocomial Infections; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Propranolol; Prospective cohort; Rattus; Recovery; Research; Research Design; Research Personnel; Risk; Rodent; Scientist; Secondary to; Signal Transduction; Surgeon; TBI Patients; Testing; Therapeutic; Time; TimeLine; Training; Translational Research; Trauma; Traumatic Brain Injury; Traumatic injury; United States National Institutes of Health; Vulnerable Populations; adverse outcome; antagonist; anti-PD-1; anti-PD1 antibodies; attenuation; base; behavior test; career; central nervous system injury; clinically relevant; cohort; controlled cortical impact; disability; experience; experimental study; femoral artery; immune function; immunoregulation; improved; improved outcome; infection risk; injured; member; model design; mortality; neuroimmunology; neuroinflammation; pre-clinical; prevent; programs; prospective; relating to nervous system; restoration; severe injury; skills; therapeutic target; therapy development; tool

PROJECT SUMMARY/ABSTRACT Critical injury, including traumatic brain injury (TBI), remains one of the most common causes of morbidity and mortality in children. Despite efforts to develop pharmacotherapy for TBI, clinical trials have proven ineffective. Improvements in outcome have largely been due to improvements in medical care. One known complication of severe TBI is nosocomial infection; the incidence may be as high as 50% with mortality as high as 37%. Even in the absence of mortality, infection can lead to secondary brain injury and poor outcomes. One cause for post- injury nosocomial infections is a profound anti-inflammatory response known as immunoparalysis. TBI is strongly associated with immunoparalysis, and more recent data suggest that patients with TBI plus systemic injury (polytrauma) are even more prone to nosocomial infection than patients with either injury alone. One pathway by which this may occur is through a neurally-mediated mechanism known as the cholinergic anti-inflammatory pathway (CAIP), which involves signaling from the brain to splenic leukocytes via the splenic nerve. Attenuation of the CAIP is a potential method for reversing immunoparalysis, but other therapeutic targets include mechanism-independent immunomodulation. Unfortunately, there is little preclinical data examining the timeline for immune suppression following injury or how reversing post-injury immune suppression may affect the injured, recovering brain. The overall goal of this proposal is to develop immunomodulatory approaches to improve outcomes through safe restoration of immune function following critical injury in children. Our central hypothesis is that post-injury immune suppression is an important acute and chronic sequela of critical injury that can be attenuated without negatively impacting neurological outcomes. Experiments will involve using a clinically relevant combined injury model in juvenile rats: an experimentally induced TBI (controlled cortical impact) followed by hemorrhage induced by aspiration of blood from the femoral artery. To perform mechanism-specific attenuation of post-traumatic immunosuppression, we propose using splenic denervation to inhibit the CAIP. As splenic denervation is clinically not practical, we will also use pharmacotherapeutic agents to target the CAIP, including treatment with an α7 nicotinic receptor antagonist (memantine) or a beta-adrenergic antagonist (propranolol). We will also examine mechanism-independent pharmacotherapy of post-traumatic immune suppression using several immunostimulants (GM-CSF, rIL-7, INF ɣ, and anti-PD-1). Finally, as the long-term immunologic effects of severe traumatic injury are poorly understood, we will quantify the persistence of immunosuppressive effects of severe trauma in both our TBI/H model and in critically injured children. This career development award will generate further preliminary data and provide me with the necessary tools to obtain research independence and further funding in the area of pediatric neurotrauma.

项目总结/摘要 包括创伤性脑损伤（TBI）在内的危重损伤仍然是发病和死亡的最常见原因之一。 儿童死亡率。尽管努力开发TBI的药物治疗，但临床试验已证明无效。 结果的改善主要归功于医疗保健的改善。一个已知的并发症 严重的TBI是医院感染，发病率可高达50%，死亡率高达37%。即使在 在没有死亡率的情况下，感染可导致继发性脑损伤和不良结局。一个原因后- 损伤医院感染是一种被称为免疫麻痹的深刻的抗炎反应。TBI强烈 与免疫麻痹相关，最近的数据表明，TBI加全身性损伤的患者 （多发伤）的患者甚至比单独损伤的患者更容易发生医院感染。一种途径 这可能是通过一种称为胆碱能抗炎的神经介导机制发生的 在一些实施方案中，免疫调节通路（CAIP）包括通过脾神经从脑到脾白细胞的信号传导。衰减 CAIP是逆转免疫麻痹的潜在方法，但其他治疗靶点包括 非机制依赖性免疫调节。不幸的是，几乎没有临床前数据检查时间轴 对于损伤后的免疫抑制或如何逆转损伤后免疫抑制可能影响受伤者， 恢复大脑。该提案的总体目标是开发免疫调节方法，以改善 通过安全恢复儿童严重损伤后的免疫功能来获得结果。我们的中央 假设是，损伤后免疫抑制是一个重要的急性和慢性后遗症的关键 可以减轻而不会对神经系统结果产生负面影响的损伤。实验将 涉及在幼年大鼠中使用临床相关的联合损伤模型：实验诱导的TBI （控制皮质撞击），随后通过从股动脉抽吸血液诱导出血。到 进行创伤后免疫抑制的机制特异性衰减，我们建议使用脾 去神经抑制CAIP。由于脾去神经在临床上不切实际，我们还将使用 靶向CAIP的药物，包括用α7烟碱受体拮抗剂治疗 （美金刚）或β-肾上腺素能拮抗剂（普萘洛尔）。我们还将研究机制独立 使用几种免疫刺激剂（GM-CSF、rIL-7、INF）的创伤后免疫抑制的药物治疗 抗PD-I）。最后，由于对严重创伤的长期免疫学影响知之甚少， 我们将在我们的TBI/H模型和TBI/H模型中量化严重创伤的免疫抑制作用的持续性。 严重受伤的孩子。这个职业发展奖将产生进一步的初步数据，并为我提供 与必要的工具，以获得研究的独立性和进一步的资金，在该地区的儿科 神经创伤