N-acetylserotonin alleviates neurotoxicity in alcohol misuse following TBI

N-乙酰血清素可减轻 TBI 后酒精滥用造成的神经毒性

基本信息

  • 批准号:
    10591834
  • 负责人:
  • 金额:
    $ 23.01万
  • 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:
    2023-05-01 至 2025-04-30
  • 项目状态:
    未结题

项目摘要

Traumatic brain injury (TBI) and comorbid alcohol use disorder (AUD) cause heavy medical, economic, and social burdens. TBI drives the escalation of alcohol intake in TBI patients and animal models. One challenge is that TBI and comorbid AUD (alcohol misuse following TBI) is difficult to manage with current treatment options. Another challenge is that the molecular mechanisms underlying alcohol misuse following TBI are lacking. Thus, it is urgently needed to explore novel therapies and molecular mechanisms for AUD following TBI. We and others reported that N-acetyl-serotonin (NAS) offers protection by targeting neurotoxicity and inflammation in various tissue injuries. However, it is unknown whether NAS alleviates AUD following TBI. The central hypothesis of this translational project is that NAS mitigates TBI-induced alcohol consumption. The overall goal is to develop a novel NAS therapy to alleviate TBI-increased alcohol intake and preference and elucidate its protective mechanisms by regulating brain-derived neurotrophic factor (BDNF), tyrosine receptor kinase B (TrkB)/Akt pathway, and inflammation. This study is supported by preliminary data and prior research: 1) NAS is a potent agonist of TrkB, and the BDNF/TrkB pathway plays an important role in alcohol consumption. 2) we and others report that NAS inhibits neurotoxicity in cultured neurons and offers protection in animal models of cerebral ischemia and retinal ischemia-reperfusion. 3) we and others reported that NAS protects hepatic cell apoptosis and hepatic ischemia-reperfusion injury and acts on circadian rhythm by TrkB activation. 4) our preliminary data suggest that NAS alleviates TBI-induced alcohol intake and preference, cognitive decline, and neurobehavioral deficit in a few mice in vivo and prevents neurotoxicity in scratch- and ethanol-treated cultured neuronal cells, a cell injury model of alcohol use following TBI in vitro. 5) we show that NAS reduces interleukin-1β (IL-1 and IL- 6 releases in scratch- and ethanol-treated astrocytes, another cell injury model of alcohol use following TBI, and 6) we found that NAS alleviates BDNF reduction in TBI-induced alcohol consumption exposed mice. Aim 1 will test whether NAS alleviates TBI-induced alcohol consumption, neurodegeneration, and cognitive and neurobehavioral impairments in mice and determine whether TrkB deficiency, at least partly, reduces NAS’s benefits in TrkB knockout mice. Aim 2 will determine whether the protective mechanisms of NAS are mediated by regulating BDNF expression, activating TrkB/Akt pathway, and inhibiting inflammation as well as the regulation of BDNF/TrkB/Akt pathway of NAS are mediated by activation of TrkB using TrkB knockout mice. The success of this study will make an important contribution to drug discovery and pathogenesis for alcohol misuse following TBI. Key strengths include: i) Usage of TBI, AUD, and TBI-induced alcohol intake and preference animal models; ii) Extensive experience in the study of NAS in a variety of tissue injuries; and iii) A strong team with interdisciplinary and complementary expertise and an excellent history of collaborative publications in the fields of AUD, alcohol consumption, inflammation, neurotoxicity, and drug development.
创伤性脑损伤(TBI)和共病酒精使用障碍(AUD)导致严重的医疗,经济和社会问题。 社会负担。TBI驱动TBI患者和动物模型中酒精摄入量的增加。一个挑战是 TBI和合并的AUD(TBI后酒精滥用)很难用目前的治疗方案进行管理。 另一个挑战是缺乏TBI后酒精滥用的分子机制。因此,在本发明中, 因此迫切需要探索TBI后AUD的新疗法和分子机制。我们和其他人 N-acetyl-serotonin(NAS)通过靶向神经毒性和炎症提供保护, 组织损伤然而,目前尚不清楚NAS是否会在TBI后重新调整AUD。这个问题的核心假设是 翻译项目是NAS减轻TBI诱导的酒精消费。总体目标是制定一个 一种新的NAS疗法,以缓解TBI增加的酒精摄入和偏好,并阐明其保护作用 通过调节脑源性神经营养因子(BDNF)、酪氨酸受体激酶B(Trk B)/Akt 途径和炎症。这项研究得到了初步数据和先前研究的支持:1)NAS是一种有效的 BDNF是TrkB的激动剂,BDNF/TrkB通路在酒精消耗中起重要作用。2)我们和其他人 报告说,NAS抑制培养的神经元的神经毒性,并提供保护,在动物模型的脑 缺血和视网膜缺血-再灌注。3)我们和其他人报道了NAS保护肝细胞凋亡 和肝脏缺血-再灌注损伤,并通过TrkB激活作用于昼夜节律。4)我们的初步数据 这表明,NAS抑制了TBI诱导的酒精摄入和偏好、认知能力下降和神经行为 在一些小鼠体内的缺陷,并防止在划痕和乙醇处理的培养神经元细胞的神经毒性, 体外TBI后酒精使用的细胞损伤模型。5)我们发现,NAS降低了白细胞介素-1 β(IL-1 β和IL-1 R)的表达, 6在划痕和乙醇处理的星形胶质细胞中释放,这是TBI后酒精使用的另一种细胞损伤模型, 6)我们发现NAS在TBI诱导的酒精消耗暴露小鼠中证实了BDNF的减少。 目标1将测试NAS是否能抑制TBI诱导的饮酒、神经退行性变和认知功能障碍。 和神经行为障碍,并确定TrkB缺乏是否至少部分地降低了NAS的 TrkB敲除小鼠的益处。目的2将确定NAS的保护机制是否介导 通过调节BDNF的表达,激活TrkB/Akt通路,抑制炎症, NAS的BDNF/TrkB/Akt途径的调节是通过使用TrkB敲除小鼠激活TrkB介导的。 该研究的成功将为酒精的药物发现和发病机制做出重要贡献 TBI后的误用。主要优势包括:i)使用TBI,AUD和TBI诱导的酒精摄入, ii)在各种组织损伤中研究NAS的广泛经验;和iii)A 强大的团队,具有跨学科和互补的专业知识,以及良好的合作历史 AUD、酒精消耗、炎症、神经毒性和药物开发领域的出版物。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Xin Wang其他文献

CD44-engineered mesoporous silica nanoparticles for overcoming multidrug resistance in breast cancer
CD44 工程介孔二氧化硅纳米粒子用于克服乳腺癌的多药耐药性
  • DOI:
    10.1016/j.apsusc.2015.01.204
  • 发表时间:
    2015-03
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Xin Wang;Ying Liu;Shouju Wang;Donghong Shi;Xianguang Zhou;Chunyan Wang;Jiang Wu;Zhiyong Zeng;Yanjun Li;Jing Sun;Ji;ong Wang;Longjiang Zhang;Zhaogang Teng;Guangming Lu
  • 通讯作者:
    Guangming Lu

Xin Wang的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Xin Wang', 18)}}的其他基金

Racial/ethnic disparities in acute myeloid leukemia survival in the novel therapy era: an exploration of the underlying mechanisms and potential targets for intervention
新疗法时代急性髓系白血病生存的种族/民族差异:探索潜在机制和潜在干预目标
  • 批准号:
    10751435
  • 财政年份:
    2023
  • 资助金额:
    $ 23.01万
  • 项目类别:
A large sample machine learning network analysis of vertex cortical thickness measures for high resolution definition of PTSD related cortical structure abnormalities
大样本机器学习网络分析顶点皮质厚度测量,以高分辨率定义 PTSD 相关皮质结构异常
  • 批准号:
    10373650
  • 财政年份:
    2022
  • 资助金额:
    $ 23.01万
  • 项目类别:
A large sample machine learning network analysis of vertex cortical thickness measures for high resolution definition of PTSD related cortical structure abnormalities
大样本机器学习网络分析顶点皮质厚度测量,以高分辨率定义 PTSD 相关皮质结构异常
  • 批准号:
    10551850
  • 财政年份:
    2022
  • 资助金额:
    $ 23.01万
  • 项目类别:
Using pre-pandemic baseline data in people with and without PTSD to study effects of the COVID-19 pandemic on mental health and brain emotion circuits
使用患有和不患有 PTSD 的人的大流行前基线数据来研究 COVID-19 大流行对心理健康和大脑情绪回路的影响
  • 批准号:
    10583520
  • 财政年份:
    2022
  • 资助金额:
    $ 23.01万
  • 项目类别:
Using pre-pandemic baseline data in people with and without PTSD to study effects of the COVID-19 pandemic on mental health and brain emotion circuits
使用患有和不患有 PTSD 的人的大流行前基线数据来研究 COVID-19 大流行对心理健康和大脑情绪回路的影响
  • 批准号:
    10372490
  • 财政年份:
    2022
  • 资助金额:
    $ 23.01万
  • 项目类别:
Study of early brain alterations that predict development of chronic PTSD
预测慢性创伤后应激障碍(PTSD)发展的早期大脑改变的研究
  • 批准号:
    10337146
  • 财政年份:
    2021
  • 资助金额:
    $ 23.01万
  • 项目类别:
Study of early brain alterations that predict development of chronic PTSD
预测慢性创伤后应激障碍(PTSD)发展的早期大脑改变的研究
  • 批准号:
    9405530
  • 财政年份:
    2016
  • 资助金额:
    $ 23.01万
  • 项目类别:
Study of early brain alterations that predict development of chronic PTSD
预测慢性创伤后应激障碍(PTSD)发展的早期大脑改变的研究
  • 批准号:
    10004715
  • 财政年份:
    2016
  • 资助金额:
    $ 23.01万
  • 项目类别:
Study of early brain alterations that predict development of chronic PTSD
预测慢性创伤后应激障碍(PTSD)发展的早期大脑改变的研究
  • 批准号:
    9260326
  • 财政年份:
    2016
  • 资助金额:
    $ 23.01万
  • 项目类别:
Longitudinal MRI study of PTSD development from days to weeks after trauma
创伤后数天至数周 PTSD 发展的纵向 MRI 研究
  • 批准号:
    8641425
  • 财政年份:
    2013
  • 资助金额:
    $ 23.01万
  • 项目类别:

相似海外基金

Co-designing a lifestyle, stop-vaping intervention for ex-smoking, adult vapers (CLOVER study)
为戒烟的成年电子烟使用者共同设计生活方式、戒烟干预措施(CLOVER 研究)
  • 批准号:
    MR/Z503605/1
  • 财政年份:
    2024
  • 资助金额:
    $ 23.01万
  • 项目类别:
    Research Grant
Early Life Antecedents Predicting Adult Daily Affective Reactivity to Stress
早期生活经历预测成人对压力的日常情感反应
  • 批准号:
    2336167
  • 财政年份:
    2024
  • 资助金额:
    $ 23.01万
  • 项目类别:
    Standard Grant
RAPID: Affective Mechanisms of Adjustment in Diverse Emerging Adult Student Communities Before, During, and Beyond the COVID-19 Pandemic
RAPID:COVID-19 大流行之前、期间和之后不同新兴成人学生社区的情感调整机制
  • 批准号:
    2402691
  • 财政年份:
    2024
  • 资助金额:
    $ 23.01万
  • 项目类别:
    Standard Grant
Migrant Youth and the Sociolegal Construction of Child and Adult Categories
流动青年与儿童和成人类别的社会法律建构
  • 批准号:
    2341428
  • 财政年份:
    2024
  • 资助金额:
    $ 23.01万
  • 项目类别:
    Standard Grant
Elucidation of Adult Newt Cells Regulating the ZRS enhancer during Limb Regeneration
阐明成体蝾螈细胞在肢体再生过程中调节 ZRS 增强子
  • 批准号:
    24K12150
  • 财政年份:
    2024
  • 资助金额:
    $ 23.01万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Understanding how platelets mediate new neuron formation in the adult brain
了解血小板如何介导成人大脑中新神经元的形成
  • 批准号:
    DE240100561
  • 财政年份:
    2024
  • 资助金额:
    $ 23.01万
  • 项目类别:
    Discovery Early Career Researcher Award
RUI: Evaluation of Neurotrophic-Like properties of Spaetzle-Toll Signaling in the Developing and Adult Cricket CNS
RUI:评估发育中和成年蟋蟀中枢神经系统中 Spaetzle-Toll 信号传导的神经营养样特性
  • 批准号:
    2230829
  • 财政年份:
    2023
  • 资助金额:
    $ 23.01万
  • 项目类别:
    Standard Grant
Usefulness of a question prompt sheet for onco-fertility in adolescent and young adult patients under 25 years old.
问题提示表对于 25 岁以下青少年和年轻成年患者的肿瘤生育力的有用性。
  • 批准号:
    23K09542
  • 财政年份:
    2023
  • 资助金额:
    $ 23.01万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Identification of new specific molecules associated with right ventricular dysfunction in adult patients with congenital heart disease
鉴定与成年先天性心脏病患者右心室功能障碍相关的新特异性分子
  • 批准号:
    23K07552
  • 财政年份:
    2023
  • 资助金额:
    $ 23.01万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Issue identifications and model developments in transitional care for patients with adult congenital heart disease.
成人先天性心脏病患者过渡护理的问题识别和模型开发。
  • 批准号:
    23K07559
  • 财政年份:
    2023
  • 资助金额:
    $ 23.01万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了