Targeting Cholinergic Deficits with Retinoic Acid after TBI

使用视黄酸治疗 TBI 后的胆碱能缺陷

基本信息

  • 批准号:
    10741924
  • 负责人:
  • 金额:
    $ 43.73万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-08-11 至 2025-07-31
  • 项目状态:
    未结题

项目摘要

ABSTRACT Cognitive deficits are a pervasive disability following traumatic brain injury (TBI). As of yet, there are no treatments to combat these sequelae. Alterations in neurochemical (neurotransmission) and white matter connectivity have been identified as two contributors to deficits in learning and memory behaviors after TBI. The neurotransmitter acetylcholine (ACh) is a crucial factor in regulation of cognitive function, specifically in learning and memory. Studies in experimental TBI have shown deficits in cholinergic function, and alterations in proteins involved with cholinergic neurotransmission. Recent studies have found that exogenous all-trans retinoic acid (ATRA), an active metabolite of vitamin A, can increase protein levels of choline acetyltransferase (ChAT), the vesicle ACh transporter (VAChT), and acetylcholinesterase (AChE). This leads us to posit that ATRA can be used as a potential therapeutic to improve cognitive behavior after experimental TBI. The primary goal of this project is to provide proof-of-concept evidence that ATRA can attenuate cholinergic deficits after TBI. Moreover, in support of this effect in the context of TBI, we provide preliminary data demonstrates that ATRA treatment can attenuates spatial memory retention deficits after experimental TBI. Cholinergic deficits may also be, at least partially, attributable to white matter damage. Neurons of the medial septum and the diagonal band of Broca innervate the hippocampus via the fimbria–fornix bundle. In experimental studies, damage to the fimbra/fornix produces cholinergic denervation in the hippocampus with concomitant deficits in cognition and ACh neurotransmission. Clinically, diffusion MRI tractography studies have found decreased fimbria/fornix integrity after TBI. Assessment of high-definition fiber tractography in preclinical TBI are well suited to understand global connectivity and represent a high translational outcome to evaluate ATRA therapy. The primary hypothesis of this project is to provide evidence that RA can attenuate cholinergic deficits after TBI. This hypothesis will be tested in two Aims to elucidate the effects of ATRA on the ACh system and assess the effect of RA on the integrity of axonal connectivity between cholinergic brain regions. Aim 1 will determine if ATRA treatment can attenuate cholinergic the loss of key cholinergic proteins important for ACh neurotransmission (AChE, ChaT) and (VAChT). To enhance the specificity of assessing ATRA’s effects on cholinergic function, a scopolamine challenge paradigm will be utilized. Scopolamine, a muscarinic receptor antagonist, is a memory disturbing agent. After experimental TBI, it has been reported that there is a reduction in the sensitivity of scopolamine to disrupt memory. In Aim 2, the effects of experimental TBI on cholinergic-associated white matter tracts, both with and without ATRA therapy, will be examined. If successful, this project will demonstrate for the first time the therapeutic utility of RA to attenuate cholinergic protein and white matter deficits after TBI.
摘要

项目成果

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C EDWARD DIXON其他文献

C EDWARD DIXON的其他文献

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{{ truncateString('C EDWARD DIXON', 18)}}的其他基金

PRECISE-TBI: PRE Clinical lnteragency research resourcE-TBI
PRECISE-TBI:PRE 临床跨机构研究资源E-TBI
  • 批准号:
    10935621
  • 财政年份:
    2021
  • 资助金额:
    $ 43.73万
  • 项目类别:
Neurogranin and Traumatic Brain Injury
神经粒蛋白和创伤性脑损伤
  • 批准号:
    10254474
  • 财政年份:
    2021
  • 资助金额:
    $ 43.73万
  • 项目类别:
Neurogranin and Traumatic Brain Injury
神经粒蛋白和创伤性脑损伤
  • 批准号:
    10512044
  • 财政年份:
    2021
  • 资助金额:
    $ 43.73万
  • 项目类别:
PRECISE-TBI: PRE Clinical lnteragency research resourcE-TBI
PRECISE-TBI:PRE 临床跨机构研究资源E-TBI
  • 批准号:
    10378331
  • 财政年份:
    2021
  • 资助金额:
    $ 43.73万
  • 项目类别:
PRECISE-TBI: PRE Clinical lnteragency research resourcE-TBI
PRECISE-TBI:PRE 临床跨机构研究资源E-TBI
  • 批准号:
    10620688
  • 财政年份:
    2021
  • 资助金额:
    $ 43.73万
  • 项目类别:
Connectome Analysis of the Nigrostriatal Neuronal Tract after Blast TBI
冲击波 TBI 后黑质纹状体神经元束的连接组分析
  • 批准号:
    10015797
  • 财政年份:
    2020
  • 资助金额:
    $ 43.73万
  • 项目类别:
Structural and Functional Dysconnectivity in Dopamine/Acetylcholine Circuitry in Repetitive Mild TBI
重复性轻度 TBI 中多巴胺/乙酰胆碱回路的结构和功能脱节
  • 批准号:
    9916055
  • 财政年份:
    2020
  • 资助金额:
    $ 43.73万
  • 项目类别:
Role of UCHL1 in Axonal Injury and Recovery after TBI
UCHL1 在 TBI 后轴突损伤和恢复中的作用
  • 批准号:
    10199060
  • 财政年份:
    2017
  • 资助金额:
    $ 43.73万
  • 项目类别:
Multifunctional rehabilitative therapy to reduce Alzheimer pathology after TBI
多功能康复治疗可减少 TBI 后阿尔茨海默病的病理变化
  • 批准号:
    10063439
  • 财政年份:
    2016
  • 资助金额:
    $ 43.73万
  • 项目类别:
Chronic Lithium Therapy for Traumatic Brain Injury
慢性锂盐治疗创伤性脑损伤
  • 批准号:
    9260706
  • 财政年份:
    2014
  • 资助金额:
    $ 43.73万
  • 项目类别:

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乙酰胆碱酯酶抑制剂对患有轻至中度阿尔茨海默病的老年人骨代谢和骨折危险因素的影响
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Acetylcholinesterase Complex Protein-Protein Interactions as Drug Targets Against Organophosphate-induced Neurotoxicity.
乙酰胆碱酯酶复合物蛋白质-蛋白质相互作用作为抗有机磷诱导的神经毒性的药物靶点。
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