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

基本信息

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
项目类别：
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

项目摘要

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）在内的严重损伤仍然是发病率和最常见的原因之一儿童死亡率。尽管努力开发用于TBI的药物疗法，但临床试验已被证明无效。结果的改善在很大程度上是由于医疗保健的改善。一个已知的并发症严重的TBI是医院感染；该事件可能高达50％，死亡率高达37％。甚至在缺乏死亡率，感染会导致继发性脑损伤和不良预后。后的原因之一损伤的医院感染是一种被称为免疫分析的深刻抗炎反应。 TBI强烈与免疫分析相关，以及最新的数据表明，TBI和全身损伤的患者（多发性毛虫）比单独的任何损伤患者更容易出现医院感染。一条路可能发生这种情况的是通过神经介导的机制称为胆碱能抗炎途径（CAIP），涉及通过脾神经从大脑到脾白细胞的信号。衰减 CAIP是逆转免疫分析的潜在方法，但其他治疗靶标包括与机理无关的免疫调节。不幸的是，几乎没有临床前数据检查时间表受伤后的免疫抑制或如何逆转伤害后免疫抑制可能会影响受伤的受伤，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受伤后的免疫功能的安全结果。我们的中心假设是伤害后免疫抑制是关键的重要急性和慢性后遗症可以减弱而不会对神经系统结局产生负面影响的损伤。实验会涉及在少年大鼠中使用临床相关的合并损伤模型：实验诱导的TBI （受控皮质影响），然后是股动脉的血液吸入引起的出血。到进行创伤后免疫抑制的特定机理衰减，我们建议使用脾脏去神经抑制咖啡。由于脾脏的神经保护在临床上是不切实际的，我们也将使用药物治疗剂以靶向CAIP，包括用α7烟碱受体拮抗剂治疗（美容）或β-肾上腺素拮抗剂（普萘洛尔）。我们还将检查与机制无关的使用几种免疫刺激剂（GM-CSF，RIL-7，INF）对创伤后免疫抑制的药物治疗 ɣ和抗PD-1）。最后，由于严重创伤性损伤的长期免疫学作用知之甚少，因此我们将量化严重创伤在我们的TBI/H模型和在重伤的孩子。该职业发展奖将产生进一步的初步数据，并为我提供使用必要的工具来获得研究独立性和进一步的资金 Neurotrauma。