Phosphodiesterase 4B Inhibition as a Therapeutic Target for Alcohol-associated Liver Disease

磷酸二酯酶 4B 抑制作为酒精相关性肝病的治疗靶点

基本信息

  • 批准号:
    10354185
  • 负责人:
  • 金额:
    $ 39.02万
  • 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:
    2023-09-25 至 2024-08-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY Alcohol-associated liver disease (ALD) is a significant health problem caused by excessive alcohol consumption. ALD is generally discovered in association with fatty liver, steatosis, or fibrosis progression, leading to cirrhosis. Unfortunately, there is no approved drug for ALD, and the current therapies rely on abstinence, immune suppressants like corticosteroids, or liver transplantation in case of advanced cirrhosis. Studies suggest that inflammation plays a significant role in ALD initiation and progression. Kupffer cells (KCs), the residing macrophages in the liver, are mainly involved in hepatic inflammatory reactions. KCs, upon contact with injured hepatocytes or gut bacterial endotoxins such as lipopolysaccharides (LPS), get activated and secrete inflammatory cytokines, including TNF-α and start the inflammation. Pharmacological inhibition of KCs by small molecules such as gadolinium chloride or decreasing intestinal bacterial load with antibiotics is shown to prevent liver injury and ALD progression. Cyclic adenosine monophosphate (cAMP) signaling plays a significant role in dampening hepatic injury and steatosis. Alcohol is known to increase the expression of cAMP degrading enzyme phosphodiesterase 4 (PDE4). The upregulated PDE4 decreases the cAMP levels and induces liver inflammation/injury. PDE4 inhibitors have been investigated to inhibit macrophage recruitment and activation in ALD; however, the current PDE4 inhibitors such as rolipram and roflumilast are associated with severe side effects, including nausea, vomiting, diarrhea, and dyspepsia. This study aims to inhibit PDE4B activity by novel inhibitor KVA-D-88 in alcohol-induced steatosis. Our preliminary data show that KVA-D-88 is a potent and selective PDE4B inhibitor with a suitable pharmacokinetic profile. The development of highly selective PDE4B inhibitors such as KVA-D-88 directly applies to human ALD. However, PDE4B inhibition in other organs, such as the brain, is known to produce severe side effects. Therefore, there is a need for KC-specific drug delivery to enhance the drug efficacy and specificity. We will develop KVA-D-88 nanoparticles for liver-specific PDE4B inhibition. Our specific aims are Aim 1 to establish the role of PDE4B inhibitor KVA-D-88 in ALD in vitro and in vivo. In this aim, we will determine the specificity of KVA-D-88 to inhibit PDE4B isotype compared to PDE4D isotype in alcohol-induced primary KCs, hepatocytes, and hepatic stellate cells (HSCs). Next, we will evaluate the effect of KVA-D-88 mediated PDE4B inhibition on cAMP signaling, TNF-α induced ER stress, and ethanol- induced toxicity in the modified NIAAA mouse model. Aim 2. Formulate and characterize KCs targeted KVA- D-88 loaded polyethylene glycol (PEG) decorated solid lipid nanoparticles (SLNs). In this aim, we will develop and characterize KCs targeted PEG-SLNs loaded with KVA-D-88. Next, we will evaluate the therapeutic efficacy of KVA-D-88 loaded SLNs in the NIAAA model. This project is highly significant as it could provide us with ALD therapy and a potential platform for nonalcoholic fatty liver disease (NAFLD) and cholestasis-induced liver fibrosis.
项目摘要 酒精相关性肝病(ALD)是由过量饮酒引起的一种严重的健康问题。 ALD通常与脂肪肝、脂肪变性或纤维化进展相关,导致肝硬化。 不幸的是,没有批准的药物治疗ALD,目前的治疗依赖于禁欲,免疫, 皮质类固醇等抑制剂,或在晚期肝硬化的情况下进行肝移植。研究表明 炎症在ALD的发生和发展中起重要作用。枯否细胞(KCs), 肝脏中的巨噬细胞主要参与肝脏炎症反应。KCs,在与受伤人员接触时 肝细胞或肠道细菌内毒素如脂多糖(LPS)被激活并分泌 炎症细胞因子,包括TNF-α,并启动炎症。小分子药物对KCs的药理学抑制 分子如氯化钆或用抗生素减少肠道细菌负荷, 肝损伤和ALD进展。环磷酸腺苷(cAMP)信号传导在细胞凋亡中起重要作用。 抑制肝损伤和脂肪变性。已知酒精可增加cAMP降解酶的表达 磷酸二酯酶4(PDE 4)。上调的PDE 4降低cAMP水平并诱导肝细胞凋亡。 炎症/损伤。已经研究了PDE 4抑制剂抑制巨噬细胞募集和活化, ALD;然而,目前的PDE 4抑制剂(例如咯利普兰和罗氟司特)与严重侧有关 副作用包括恶心、呕吐、腹泻和消化不良。本研究的目的是通过新的PDE 4 B抑制剂来抑制PDE 4 B活性。 抑制剂KVA-D-88在酒精诱导的脂肪变性中的作用。我们的初步数据表明,KVA-D-88是一种有效的, 具有合适药代动力学特征的选择性PDE 4 B抑制剂。高选择性PDE 4 B的开发 抑制剂如KVA-D-88直接应用于人ALD。然而,PDE 4 B在其他器官中的抑制,如 大脑会产生严重的副作用因此,需要KC特异性药物递送, 提高了药物的疗效和特异性。我们将开发用于肝脏特异性PDE 4 B的KVA-D-88纳米颗粒 抑制作用我们的具体目标是目标1,以确定PDE 4 B抑制剂KVA-D-88在体外ALD中的作用, in vivo.为此,我们将确定KVA-D-88与PDE 4D相比抑制PDE 4 B同种型的特异性 同种型在酒精诱导的原代KC、肝细胞和肝星状细胞(HSC)中。接下来,我们将评估 KVA-D-88介导的PDE 4 B抑制对cAMP信号传导、TNF-α诱导的ER应激和乙醇- 在改良的NIAAA小鼠模型中诱导毒性。目标二。配制和表征靶向KVA的KC- D-88负载聚乙二醇(PEG)修饰的固体脂质纳米粒(SLN)。为此,我们将 开发和表征负载KVA-D-88的靶向KCs的PEG-SLN。接下来,我们将评估 在NIAAA模型中负载KVA-D-88的SLN的功效。这个项目非常重要,因为它可以为我们提供 ALD治疗和非酒精性脂肪肝(NAFLD)和胆汁淤积诱导的潜在平台 肝纤维化

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 }}

Virender Kumar其他文献

Virender Kumar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('Virender Kumar', 18)}}的其他基金

Targeting PI3K/BRD4 and Hedgehog Pathway in Alcohol Associated Liver Disease
靶向 PI3K/BRD4 和 Hedgehog 通路治疗酒精相关性肝病
  • 批准号:
    10351877
  • 财政年份:
    2021
  • 资助金额:
    $ 39.02万
  • 项目类别:
Targeting PI3K/BRD4 and Hedgehog Pathway in Alcohol Associated Liver Disease
靶向 PI3K/BRD4 和 Hedgehog 通路治疗酒精相关性肝病
  • 批准号:
    10686248
  • 财政年份:
    2021
  • 资助金额:
    $ 39.02万
  • 项目类别:

相似海外基金

StuDy AimED at Increasing AlCohol AbsTinEnce (DEDICATE)
旨在提高酒精戒断率的研究(奉献)
  • 批准号:
    10577022
  • 财政年份:
    2023
  • 资助金额:
    $ 39.02万
  • 项目类别:
A Controlled Study of Extended Cannabis Abstinence in Major Depression
重度抑郁症患者长期吸食大麻的对照研究
  • 批准号:
    478313
  • 财政年份:
    2023
  • 资助金额:
    $ 39.02万
  • 项目类别:
    Operating Grants
Exercised-induced modulation of insular cortex microcircuitry during alcohol abstinence
戒酒期间运动诱导的岛叶皮质微电路调节
  • 批准号:
    10748763
  • 财政年份:
    2023
  • 资助金额:
    $ 39.02万
  • 项目类别:
Prapela™ SVS: A cost-effective stochastic vibrotactile stimulation device toimprove the clinical course of infants with neonatal abstinence syndrome.
Prapela™ SVS:一种经济高效的随机振动触觉刺激装置,可改善患有新生儿戒断综合征的婴儿的临床过程。
  • 批准号:
    10837421
  • 财政年份:
    2023
  • 资助金额:
    $ 39.02万
  • 项目类别:
Enforced alcohol abstinence: does it reduce reoffending?
强制戒酒:会减少再犯罪吗?
  • 批准号:
    ES/X003566/1
  • 财政年份:
    2023
  • 资助金额:
    $ 39.02万
  • 项目类别:
    Fellowship
Neurobiological impact of acute digital media abstinence among drug using college students
吸毒大学生急性数字媒体戒断的神经生物学影响
  • 批准号:
    10677380
  • 财政年份:
    2023
  • 资助金额:
    $ 39.02万
  • 项目类别:
Single-cell whole brain imaging of nicotine intoxication, dependence, and abstinence
尼古丁中毒、依赖和戒断的单细胞全脑成像
  • 批准号:
    10588509
  • 财政年份:
    2023
  • 资助金额:
    $ 39.02万
  • 项目类别:
Understanding recovery from alcohol use disorder: Longitudinal observation of two voluntary temporary abstinence periods
了解酒精使用障碍的恢复:两个自愿临时戒酒期的纵向观察
  • 批准号:
    10740677
  • 财政年份:
    2023
  • 资助金额:
    $ 39.02万
  • 项目类别:
Sleep Disturbances During Cocaine Abstinence, Dopamine Adaptations, and Motivation for Cocaine
可卡因戒断期间的睡眠障碍、多巴胺适应和可卡因动机
  • 批准号:
    10681668
  • 财政年份:
    2023
  • 资助金额:
    $ 39.02万
  • 项目类别:
Transcriptional adaptations driving the intensification of alcohol-seeking in dependent rats undergoing prolonged abstinence
转录适应导致长期戒酒的依赖性大鼠对酒精的渴求加剧
  • 批准号:
    10540014
  • 财政年份:
    2022
  • 资助金额:
    $ 39.02万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了