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: 10608140
• 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/10608140
• 关键词: Acute; Adolescent; Adrenergic beta-Antagonists; Affect; Animal Model; Animals; Anti-Inflammatory Agents; Area; Attenuated; Blood; Brain; Brain Injuries; Caring; Cause of Death; Cells; Central Nervous System; Cephalic; 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; Hypovolemics; IL7 gene; Immune; Immune Targeting; Immunohistochemistry; Immunologic Adjuvants; Immunologics; Immunology; Immunophenotyping; Immunosuppression; Impaired cognition; Impairment; Incidence; Infection; Inflammation; Inflammatory Response; Injury; Interferon Type II; K-Series Research Career Programs; Leukocytes; Life; Mediating; Medical; Memantine; Mentors; Methods; Modeling; Morbidity - disease rate; Multiple Trauma; Nerve; Nervous System Trauma; Neurocognitive; Neurological outcome; Nicotinic Receptors; Nosocomial Infections; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Propranolol; Prospective cohort; Rattus; Recovery; Research; Research Design; Research Personnel; Risk; Rodent; Scientist; Secondary to; Signal Transduction; Surgeon; TBI Patients; Testing; Therapeutic; Time; 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; aspirate; attenuation; behavior test; career; central nervous system injury; cholinergic; clinically relevant; cohort; controlled cortical impact; disability; education planning; experience; experimental study; femoral artery; immune function; immune stimulatory agent; immunoregulation; improved; improved outcome; infection risk; injured; member; model design; mortality; neural; neuroimmunology; neuroinflammation; pharmacologic; pre-clinical; prevent; programs; prospective; restoration; severe injury; skills; therapeutic target; therapy development; timeline; 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.

项目摘要/摘要 包括创伤性脑损伤(TBI)在内的危重损伤仍然是最常见的致病原因之一。 儿童死亡率。尽管努力开发治疗脑损伤的药物，但临床试验被证明无效。 结果的改善在很大程度上是由于医疗保健的改善。一个已知的并发症是 重型颅脑损伤为医院感染，发病率高达50%，病死率高达37%。即使是在 无死亡、感染可导致继发性脑损伤和不良预后。开机自检的一个原因- 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是强有力的 与免疫麻痹有关，最近的数据表明，脑外伤合并全身损伤的患者 (多发伤)甚至比单独受伤的患者更容易发生医院感染。一条路径 这可能是通过一种被称为胆碱能抗炎的神经中介机制来实现的。 途径(CAIP)，涉及从大脑通过脾神经向脾白细胞发出信号。衰减 是一种潜在的逆转免疫麻痹的方法，但其他治疗靶点包括 不依赖机制的免疫调节。不幸的是，几乎没有临床前的数据来检验这一时间表。 关于损伤后的免疫抑制或逆转损伤后的免疫抑制可能如何影响伤者， 恢复中的大脑。这项提案的总体目标是开发免疫调节方法，以改善 儿童危重损伤后安全恢复免疫功能的结果。我们的中央 假设损伤后免疫抑制是危重病的重要急慢性后遗症 可以在不对神经结果产生负面影响的情况下得到减轻的损伤。实验将会 采用临床相关的幼年大鼠复合伤模型：实验性颅脑损伤 (受控皮质撞击)，随后是股动脉抽血引起的出血。至 实施创伤后免疫抑制的特定机制减弱，我们建议使用脾 去神经以抑制CAIP。由于去脾神经在临床上是不可行的，我们也将使用 针对CAIP的药物治疗药物，包括使用α7尼古丁受体拮抗剂治疗 (美金刚)或β-肾上腺素能拮抗剂(心得安)。我们还将研究独立于机制的 几种免疫刺激剂(GM-CSF、rIL-7、INF)治疗创伤后免疫抑制 ɣ和抗PD-1)。最后，由于人们对严重创伤的长期免疫影响知之甚少， 我们将量化严重创伤的免疫抑制效应在我们的TBI/H模型和 受重伤的儿童。这个职业发展奖将产生更多的初步数据，并为我提供 拥有必要的工具以获得儿科领域的研究独立性和进一步的资金 神经创伤。