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：
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
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/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

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.

项目概要/摘要严重损伤，包括创伤性脑损伤 (TBI)，仍然是发病和死亡的最常见原因之一。尽管努力开发治疗 TBI 的药物疗法，但临床试验已证明无效。结果的改善主要归功于医疗护理的改善。严重的TBI是院内感染，发生率可能高达50%，死亡率甚至高达37%。如果没有死亡，感染可能导致继发性脑损伤和术后不良后果的原因之一。损伤院内感染是一种强烈的抗炎反应，称为免疫麻痹。与免疫麻痹相关，最近的数据表明 TBI 加上全身损伤的患者（多发伤）比仅受任一途径损伤的患者更容易发生院内感染。这种情况的发生是通过一种称为胆碱能抗炎的神经介导机制途径（CAIP），涉及通过脾神经从大脑到脾白细胞的信号传导。 CAIP 的治疗是逆转免疫麻痹的潜在方法，但其他治疗靶点包括不幸的是，几乎没有临床前数据检验时间线。受伤后的免疫抑制或逆转受伤后免疫抑制可能如何影响受伤者，该提案的总体目标是开发免疫调节方法来改善大脑。我们的中心是通过儿童严重受伤后免疫功能的安全恢复来实现结果。假设认为，损伤后免疫抑制是危重病的一个重要的急性和慢性后遗症。可以减轻损伤而不会对神经系统结果产生负面影响。涉及在幼年大鼠中使用临床联合相关损伤模型：实验诱导的 TBI （受控的皮质冲击），然后从股动脉抽吸血液引起出血。进行创伤后免疫抑制的机制特异性减弱，我们建议使用脾脏由于去脾神经术在临床上不实用，我们还将使用去神经术来抑制 CAIP。针对 CAIP 的药物治疗剂，包括使用 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）我们还将检查机制独立性。使用多种免疫刺激剂（GM-CSF、rIL-7、INF）进行创伤后免疫抑制的药物治疗最后，由于对严重创伤性损伤的长期免疫学影响知之甚少，我们将在 TBI/H 模型和 TBI/H 模型中量化严重创伤免疫抑制作用的持续性。该职业发展奖将产生进一步的初步数据并为我提供。拥有必要的工具来获得儿科领域的研究独立性和进一步的资助神经外伤。