Role of Peripheral Inflammation in TBI Pathobiology
Role of Peripheral Inflammation in TBI Pathobiology
批准号:
10375953
负责人:
PRAMOD K DASH
金额:
$51.0万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-02-01 至 2027-01-31
关键词:
AcetylcholineAcuteAddressAnimalsAnti-Inflammatory AgentsAttenuatedBindingBiologicalBloodBlood CirculationBrain DiseasesBrain InjuriesBrain PathologyBrain StemCARTPT geneCationsCellsCholinergic ReceptorsClustered Regularly Interspaced Short Palindromic RepeatsCognitiveDiseaseDoseFemaleFunctional disorderG-Protein-Coupled ReceptorsHalf-LifeHourHumanImmuneImpaired cognitionInfiltrationInflammationInflammatoryInjectionsInterleukin-1 betaIntravenousLeadLearningLipopolysaccharidesMeasuresMediatingMemoryMemory impairmentModelingMusNerve DegenerationNeuronsNeuropeptidesNeurotransmittersOrgan failureOutcomePathologyPeptide antibodiesPeptidesPeripheralPersonsPlayPublic HealthQuality of lifeRegulationReportingResearchRodentRoleSecond Messenger SystemsSecondary toSepsisSerumSiteSpleenSystemTBI treatmentTNF geneTestingTimeTraumatic Brain InjuryTumor-infiltrating immune cellsVagus nerve structurealpha-bungarotoxin receptoraxon injuryblood-brain barrier permeabilizationcytokinedesensitizationdisabilitydorsal motor nucleusexperimental studyimmunoreactivityimprovedintraperitonealintravenous administrationmalemortalityneuron lossneuronal survivalneuroprotectionreceptorscreeningsexsurvival outcometherapeutic evaluationtranscriptome sequencingvagus nerve stimulation
中文摘要
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。
英文摘要
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.
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Role of Peripheral Inflammation in TBI Pathobiology
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批准号:10553222
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海外基金