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

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

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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，被认为会导致疾病病理。不受管制的炎症会导致创伤后的继发性脑损伤和神经退行性脑损伤（TBI）。尽管大多数TBI研究都集中于中枢炎症在TBI中的作用病理生理学，周围感染的贡献正在研究中。有害的角色 Helen Bramlett及其同事首先证明了外围炎症，他们报告说腹膜内施用促炎性细胞因子对TBI动物可能导致不良结果。以前的研究表明，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，一种用于研究注射，败血症和器官衰竭的广泛模型。随后的研究表明，乙酰胆碱从迷走神经效应中的释放会刺激α7烟碱乙酰胆碱受体（α7NACHR）在炎症细胞上，导致促炎的释放降低细胞因子进入循环。由于乙酰胆碱释放后迅速降解，并且α7NACHR迅速进行脱敏，其他机制可能涉及调节外周炎症。我们检查了迷走效效率及其细胞体位于迷走神经的背运动核（DMN）中的表达神经肽，通常与神经递质共同发行，并具有相对较长的半衰期。我们已经发现可卡因和苯丙胺调节的转录本（CART）肽（CARTP）在高度表达 DMN神经元的水平。我们建议检验该CARTP调节外围的假设炎症，可用于改善TBI结果。我们将首先通过检查角色来检验这一假设使用中和CARTP抗体和给药外源CARTP针对脾脏。使用CRISPR-CAS，我们将删除DMN中的Cartpt基因，并将其删除 TBI后将测量循环促炎细胞因子的水平。然后我们将测试治疗通过检查其对感染的影响，血液脑屏障（BBB），CARTP作为TBI治疗的潜力渗透性和炎症细胞浸润到受伤的大脑中。最后，我们将检查TBI后CARTP是否给药可以减少神经元丧失并改善认知结果。性别作为生物变量将是评估。这些研究的结果不仅对TBI以及众多炎症是其他疾病。