Role of Peripheral Inflammation in TBI Pathobiology

外周炎症在 TBI 病理学中的作用

基本信息

批准号：
10553222
负责人：
PRAMOD K DASH
金额：
$ 51万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
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：
2022-02-01 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10553222
关键词：
Acetylcholine Acute Address Animals Anti-Inflammatory Agents Attenuated Binding Biological Blood Brain Diseases Brain Injuries Brain Pathology Brain Stem CARTPT gene Cations Cells Cholinergic Receptors Circulation Clustered Regularly Interspaced Short Palindromic Repeats Cognitive Disease Dose Female Functional disorder G-Protein-Coupled Receptors Half-Life Hour Human Immune Impaired cognition Infiltration Inflammation Inflammatory Injections Interleukin-1 beta Intravenous Learning Lipopolysaccharides Measures Mediating Memory Memory impairment Modeling Mus Nerve Nerve Degeneration Neurons Neuropeptides Neurotransmitters Organ failure Outcome Pathology Peptide antibodies Peptides Peripheral Persons Public Health Quality of life Regulation Reporting Research Rodent Role Second Messenger Systems Secondary to Sepsis Serum Site Spleen System TBI treatment TNF gene Testing Time Traumatic Brain Injury Vagus nerve structure alpha-bungarotoxin receptor axon injury blood-brain barrier permeabilization cytokine desensitization disability dorsal motor nucleus experimental study immune cell infiltrate immunoreactivity improved intraperitoneal intravenous administration male mortality neuron loss neuronal survival neuroprotection receptor screening sex therapeutic evaluation transcriptome sequencing vagus nerve stimulation

项目摘要

Abstract Inflammation is associated with most brain diseases and is thought to contribute to disease pathology. Unregulated inflammation can contribute to secondary brain damage and neurodegeneration following traumatic brain injury (TBI). While the majority of TBI research has focused on the role of central inflammation in TBI pathophysiology, the contribution of peripheral inflammation is under investigated. A detrimental role for peripheral inflammation was first demonstrated by Helen Bramlett and colleagues, who reported that intraperitoneal administration of pro-inflammatory cytokines to TBI animals can result in poor outcome. Previous studies have shown that vagus nerve stimulation can reduce both peripheral inflammation and mortality following bacterial lipopolysaccharide (LPS) injection, a widely used model to study inflammation, sepsis and organ failure. Subsequent studies have shown that release of acetylcholine from vagus efferents stimulates α7 nicotinic acetylcholine receptors (α7nAChR) on inflammatory cells, leading to reduced release of pro-inflammatory cytokines into the circulation. As acetylcholine is rapidly degraded after release, and α7nAChR undergo rapid desensitization, additional mechanisms may be involved in regulating peripheral inflammation. We examined the vagus efferents and their cell bodies located in the dorsal motor nucleus of vagus (DMN) for the expression of neuropeptides, which are often co-released with neurotransmitters and have a relatively longer half-lives. We have found that cocaine- and amphetamine-regulated transcript (CART) peptide (CARTp) is expressed at high levels in DMN neurons. We propose to test the hypothesis that that CARTp acts to regulate peripheral inflammation and can be used to improve TBI outcome. We will first test this hypothesis by examining the role of vagus CARTp in TBI-associated inflammation using neutralizing CARTp antibodies and administration of exogenous CARTp targeted to the spleen. Using CRISPR-Cas, we will delete the Cartpt gene in the DMN, and will measure the levels of circulating pro-inflammatory cytokines following TBI. We will then test the therapeutic potential of CARTp as a treatment for TBI by examining its effect on inflammation, blood brain barrier (BBB) permeability, and inflammatory cell infiltration into the injured brain. Finally, we will examine if post-TBI CARTp administration can reduce neuronal loss and improve cognitive outcome. Sex as a biological variable will be assessed. The results from these studies will have implications not only for TBI, as well as for the numerous other diseases in which inflammation is a contributor.

抽象的炎症与大多数脑部疾病有关，并且被认为与疾病病理有关。不受控制的炎症可能导致继发性脑损伤和创伤后神经退行性变脑损伤（TBI），而大多数 TBI 研究都集中在中枢炎症在 TBI 中的作用。病理生理学中，外周炎症的作用正在研究中。 Helen Bramlett 及其同事首先证明了外周炎症，他们报告说对 TBI 动物进行腹腔注射促炎细胞因子可能会导致不良结果。研究表明，迷走神经刺激可以减少周围炎症和死亡率细菌脂多糖 (LPS) 注射液是一种广泛用于研究炎症、脓毒症和器官衰竭的模型。随后的研究表明，迷走神经传出神经释放乙酰胆碱会刺激α7烟碱炎症细胞上的乙酰胆碱受体 (α7nAChR)，导致促炎细胞释放减少由于乙酰胆碱释放后迅速降解，α7nAChR 快速降解。脱敏，我们检查了其他机制可能涉及调节外周炎症。迷走神经传出神经及其细胞体位于迷走神经背运动核（DMN）中，用于表达神经肽通常与神经递质共同释放，并且半衰期相对较长。发现可卡因和安非他明调节转录物 (CART) 肽 (CARTp) 在高表达我们建议检验 CARTp 调节外周神经元的假设。我们将首先通过检验其作用来检验这一假设。使用中和 CARTp 抗体和施用迷走神经 CARTp 在 TBI 相关炎症中的作用使用 CRISPR-Cas 靶向脾脏的外源 CARTp，我们将删除 DMN 中的 Cartpt 基因，并且将测量 TBI 后循环促炎细胞因子的水平，然后我们将测试治疗方法。通过检查 CARTp 对炎症、血脑屏障 (BBB) 的影响，CARTp 作为治疗 TBI 的潜力最后，我们将检查 TBI 后 CARTp 是否存在。给药可以减少神经元损失并改善认知结果。这些研究的结果不仅会对 TBI 产生影响，也会对许多人产生影响。炎症是导致其他疾病的因素。