Role of Peripheral Inflammation in TBI Pathobiology

外周炎症在 TBI 病理学中的作用

• 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
• 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

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.

摘要 炎症与大多数脑部疾病有关，并被认为有助于疾病病理学。 不受调节的炎症可导致创伤后继发性脑损伤和神经退行性变 脑损伤（TBI）。虽然大多数TBI研究都集中在TBI中中枢炎症的作用， 在病理生理学方面，正在研究外周炎症的作用。有害作用， 外周炎症首先由Helen Bramlett及其同事证实， 腹膜内给予TBI动物促炎细胞因子可能导致不良结果。先前 研究表明迷走神经刺激可以减少外周炎症和死亡率 细菌脂多糖（LPS）注射，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，从迷走神经传出神经释放乙酰胆碱刺激α7烟碱 乙酰胆碱受体（α 7 nAChR）的炎症细胞，导致减少释放促炎 细胞因子进入循环系统。由于乙酰胆碱释放后迅速降解，α 7 nAChR迅速降解， 脱敏，其他机制可能参与调节外周炎症。我们研究 迷走神经传出纤维及其胞体位于迷走神经背侧运动核（DMN）， 神经肽通常与神经递质共同释放，半衰期相对较长。我们 已经发现可卡因和安非他明调节的转录物（CART）肽（CART p）在高水平表达， DMN神经元的水平。我们建议检验CARTp调节外周血淋巴细胞增殖的假设， 炎症，并可用于改善TBI的结果。我们将首先通过检查角色来验证这一假设 在TBI相关炎症中使用中和CARTp抗体和施用 靶向脾脏的外源性CARTp。使用CRISPR-Cas，我们将删除DMN中的Cartpt基因， 将测量TBI后循环促炎细胞因子的水平。然后我们将测试 通过检查CARTp对炎症、血脑屏障（BBB）的作用， 渗透性和炎性细胞浸润到受伤的大脑中。最后，我们将检查TBI后CARTp 给药可减少神经元损失并改善认知结果。性别作为一个生物学变量， 评估。这些研究的结果不仅对TBI，而且对许多 炎症是促成因素的其他疾病。