Transforming Clinical Pain Control by Targeting a Novel Non-Neuronal Receptor

通过靶向新型非神经元受体改变临床疼痛控制

基本信息

  • 批准号:
    7569660
  • 负责人:
  • 金额:
    $ 18.94万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-05-15 至 2011-04-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Opioid-induced glial activation, which compromises pain treatment and contributes to the development of drug addiction and abuse, is regulated via a signaling pathway downstream of toll-like receptor-4 (TLR4), a membrane spanning receptor that functions in complex with its accessory protein MD-2. As current opioid pharmacotherapeutics have failed to control pain while avoiding the negative consequences, there is an urgent need to understand opioid dysregulation via TLR4. The central hypothesis of the current proposal is that disruption of the TLR-4/MD-2 complex formation can inhibit opioid-induced glial activation, thereby enhancing analgesia and reducing opioid tolerance and dependence. The rationale underlying the proposed research is that the identified TLR4 inhibitors, which selectively block the critical protein-protein interactions between TLR4 and MD-2, will provide a useful tool for investigating the role of the TLR4-mediated signaling pathway in glial activation. The proposed research is innovative because it is the first drug discovery approach attempting to regulate opioid-induced glial activation. The proposed high risk/high reward approach, if successful, is projected to yield significant novel outcomes. First, the results will shed light on the mechanism of the clinically relevant opioid-induced glial activation. Second, if successful, the peptide and peptidomimetic antagonists of the TLR4/MD-2 interactions identified in the proposed research can serve as prototypes for more drug-like small-molecule inhibitors. These inhibitors may eventually find application in the development of novel therapeutics to enhance the clinical efficacy of opioid analgesics and to treat opioid addiction and abuse, as well as other clinically relevant indications. The proposed studies are built on the complementary strength of the PI in the design, synthesis, and evaluation of novel protein-protein interaction inhibitors, and of the Co-PI, who has extensive expertise in glial neurobiology and will provide support in animal testing of the identified inhibitors. In Aim 1, antagonists of TLR4 that block the TLR4/MD-2 complex formation will be developed. The working hypothesis here is that conformationally strained peptides derived from the TLR4-binding region of MD-2 can compete with the full-length MD-2 protein and thereby inhibit the TLR4/MD-2 interaction. In Aim 2, the second working hypothesis, that the inhibitors of the TLR4/MD-2 interactions can non-competitively antagonize opioids to block TLR4-mediated glial activation, will be tested. Cellular assays and animal models will be used to evaluate the inhibition of glial activation by the TLR4 antagonists both in vitro and in vivo. The proposed research is significant because it is expected to establish the TLR4/MD-2 protein-protein complex as a novel therapeutic target for preventing and treating opioid abuse. Regarding its positive impact on scientific advancements, this work will (1) improve scientific understanding of drug dependence and pain suppression and (2) allow the development of a new generation of therapeutics. PUBLIC HEALTH RELEVANCE: We aim to unravel the mechanism of opioid-induced glial activation that importantly contributes to the development of drug addiction and abuse. As an outcome of the proposed investigations, we expect to attain a better understanding of the molecular mechanisms of opioid-induced glial activation, and to clarify novel targets to regulate such activation. The intellectual merit of the proposed work lies not only in its scientific advancements in the field of chemical biology and protein engineering, but also in its potential impact on clinical applications. This work will (1) improve scientific understanding of drug dependence and pain suppression; and (2) allow the development of a new generation of therapeutics.
描述(由申请人提供):阿片类药物诱导的神经胶质细胞活化,其损害疼痛治疗并有助于药物成瘾和滥用的发展,通过toll样受体-4(TLR 4)下游的信号传导途径进行调节,TLR 4是一种跨膜受体,与其辅助蛋白MD-2复合发挥作用。由于目前的阿片类药物治疗未能在避免负面后果的同时控制疼痛,因此迫切需要了解通过TLR 4的阿片类药物失调。目前建议的中心假设是TLR-4/MD-2复合物形成的破坏可以抑制阿片类药物诱导的胶质细胞活化,从而增强镇痛作用并降低阿片类药物耐受性和依赖性。提出的研究的基本原理是,确定的TLR 4抑制剂,选择性地阻断TLR 4和MD-2之间的关键蛋白质-蛋白质相互作用,将提供一个有用的工具,研究TLR 4介导的信号通路在胶质细胞活化中的作用。这项研究具有创新性,因为它是第一个试图调节阿片类药物诱导的神经胶质激活的药物发现方法。拟议的高风险/高回报方法如果成功,预计将产生重大的新成果。首先,结果将阐明临床相关的阿片类药物诱导的神经胶质细胞活化的机制。其次,如果成功的话,在拟议的研究中确定的TLR 4/MD-2相互作用的肽和肽模拟物拮抗剂可以作为更多药物样小分子抑制剂的原型。这些抑制剂可能最终应用于开发新的治疗方法,以提高阿片类镇痛药的临床疗效,并治疗阿片类成瘾和滥用,以及其他临床相关适应症。拟定的研究建立在PI在新型蛋白质-蛋白质相互作用抑制剂的设计、合成和评价方面的互补优势之上,而Co-PI在神经胶质神经生物学方面具有广泛的专业知识,并将为已鉴定抑制剂的动物试验提供支持。在目的1中,将开发阻断TLR 4/MD-2复合物形成的TLR 4拮抗剂。这里的工作假设是,来自MD-2的TLR 4结合区的构象应变肽可以与全长MD-2蛋白竞争,从而抑制TLR 4/MD-2相互作用。在目标2中,将测试第二个工作假设,即TLR 4/MD-2相互作用的抑制剂可以非竞争性地拮抗阿片类药物以阻断TLR 4介导的神经胶质活化。将使用细胞测定和动物模型来评价TLR 4拮抗剂在体外和体内对神经胶质活化的抑制。这项研究具有重要意义,因为它有望将TLR 4/MD-2蛋白质-蛋白质复合物作为预防和治疗阿片类药物滥用的新靶点。关于其对科学进步的积极影响,这项工作将(1)提高对药物依赖和疼痛抑制的科学理解,(2)允许开发新一代治疗方法。公共卫生相关性:我们的目标是解开阿片类药物诱导的神经胶质细胞激活的机制,这对药物成瘾和滥用的发展有重要贡献。作为拟议的调查的结果,我们希望达到更好地了解阿片类药物诱导的神经胶质细胞激活的分子机制,并澄清新的目标来调节这种激活。拟议工作的智力价值不仅在于其在化学生物学和蛋白质工程领域的科学进步,还在于其对临床应用的潜在影响。这项工作将(1)提高对药物依赖和疼痛抑制的科学理解;(2)允许开发新一代治疗方法。

项目成果

期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(1)

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Hang Hubert Yin其他文献

Hang Hubert Yin的其他文献

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{{ truncateString('Hang Hubert Yin', 18)}}的其他基金

Dissecting Cell Signaling Mediated by Protein-Protein Interactions in Membranes
解析膜中蛋白质-蛋白质相互作用介导的细胞信号传导
  • 批准号:
    8797241
  • 财政年份:
    2013
  • 资助金额:
    $ 18.94万
  • 项目类别:
Dissecting Cell Signaling Mediated by Protein-Protein Interactions in Membranes
解析膜中蛋白质-蛋白质相互作用介导的细胞信号传导
  • 批准号:
    8721453
  • 财政年份:
    2013
  • 资助金额:
    $ 18.94万
  • 项目类别:
Dissecting Cell Signaling Mediated by Protein-Protein Interactions in Membranes
解析膜中蛋白质-蛋白质相互作用介导的细胞信号传导
  • 批准号:
    8416905
  • 财政年份:
    2013
  • 资助金额:
    $ 18.94万
  • 项目类别:
Exogenous Chemical Probes of TLR-Mediated Neuroinflammation
TLR 介导的神经炎症的外源化学探针
  • 批准号:
    8589736
  • 财政年份:
    2012
  • 资助金额:
    $ 18.94万
  • 项目类别:
Exogenous Chemical Probes of TLR-Mediated Neuroinflammation
TLR 介导的神经炎症的外源化学探针
  • 批准号:
    8768472
  • 财政年份:
    2012
  • 资助金额:
    $ 18.94万
  • 项目类别:
Exogenous Chemical Probes of TLR-Mediated Neuroinflammation
TLR 介导的神经炎症的外源化学探针
  • 批准号:
    8436079
  • 财政年份:
    2012
  • 资助金额:
    $ 18.94万
  • 项目类别:
Developing Small-Molecule Probes for Opioid-Induced Glial Activation
开发用于阿片类药物诱导的神经胶质激活的小分子探针
  • 批准号:
    7943002
  • 财政年份:
    2009
  • 资助金额:
    $ 18.94万
  • 项目类别:
Transforming Clinical Pain Control by Targeting a Novel Non-Neuronal Receptor
通过靶向新型非神经元受体改变临床疼痛控制
  • 批准号:
    7826624
  • 财政年份:
    2009
  • 资助金额:
    $ 18.94万
  • 项目类别:
Probing Opioid-Induced Glial Activation with Peptide Antagonists
用肽拮抗剂探测阿片类药物诱导的神经胶质激活
  • 批准号:
    7778132
  • 财政年份:
    2009
  • 资助金额:
    $ 18.94万
  • 项目类别:
Optimizing the Clinical Efficacy of Opioids by TLR4 Blockade
通过 TLR4 阻断优化阿片类药物的临床疗效
  • 批准号:
    7707898
  • 财政年份:
    2009
  • 资助金额:
    $ 18.94万
  • 项目类别:

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