权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
7826624
负责人：
Hang Hubert Yin
金额：
$ 18.94万
依托单位：
UNIVERSITY OF COLORADO
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

来源：
https://reporter.nih.gov/project-details/7826624
关键词：
Absence of pain sensation Animal Model Animal Testing Basic Science Binding Biology Blood Cellular Assay Chemicals Clinical Complex Dependence Development Drug Addiction Evaluation Future Generations Goals In Vitro Investigation Length Light Lymphocyte Antigen 96 Measures Mediating Membrane Meperidine Methadone Molecular Morphine Neurobiology Neuroglia Neurons Opiate Addiction Opioid Opioid Analgesics Outcome Oxycodone Pain Pain management Peptides Pharmaceutical Chemistry Pharmaceutical Preparations Preclinical Testing Protein Engineering Regulation Research Role Series Signal Pathway Signal Transduction Syndrome System Testing Therapeutic Validation Work clinical application clinical efficacy clinically relevant design drug development drug discovery high reward high risk improved in vitro Assay in vivo inhibitor/antagonist innovation insight interest new therapeutic target novel novel strategies novel therapeutics opioid abuse peptidomimetics prevent protein complex protein protein interaction prototype public health relevance receptor receptor function response small molecule therapeutic development toll-like receptor 4 tool

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）：阿片诱导的胶质细胞激活，影响疼痛治疗并促进药物成瘾和滥用的发展，是通过toll样受体-4 （TLR4）下游的信号通路调节的，TLR4是一种膜跨越受体，与其辅助蛋白MD-2复合物起作用。由于目前的阿片类药物治疗未能在控制疼痛的同时避免不良后果，因此迫切需要通过TLR4来了解阿片类药物的失调。目前研究的核心假设是，破坏TLR-4/MD-2复合物的形成可以抑制阿片诱导的胶质细胞激活，从而增强镇痛作用，减少阿片耐受性和依赖性。这项研究的基本原理是，鉴定出的TLR4抑制剂选择性地阻断了TLR4和MD-2之间的关键蛋白-蛋白相互作用，将为研究TLR4介导的信号通路在胶质细胞激活中的作用提供有用的工具。拟议的研究是创新的，因为它是第一个药物发现方法，试图调节阿片类药物诱导的胶质细胞激活。建议的高风险/高回报方法，如果成功，预计将产生重大的新结果。首先，这些结果将阐明临床相关阿片诱导的胶质细胞激活的机制。其次，如果成功的话，本研究中发现的TLR4/MD-2相互作用的肽和拟肽拮抗剂可以作为更多类似药物的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药物，以提高阿片类镇痛药的临床疗效，治疗阿片类药物成瘾和滥用，以及其他临床相关适应症。拟议的研究是建立在PI在设计、合成和评估新型蛋白质-蛋白质相互作用抑制剂方面的互补优势，以及Co-PI在胶质神经生物学方面拥有广泛的专业知识，并将在确定的抑制剂的动物试验中提供支持。在Aim 1中，将开发阻断TLR4/MD-2复合物形成的TLR4拮抗剂。这里的工作假设是，来自MD-2的TLR4结合区域的构象张力肽可以与全长MD-2蛋白竞争，从而抑制TLR4/MD-2相互作用。在Aim 2中，将测试第二个有效假设，即TLR4/MD-2相互作用的抑制剂可以非竞争性地拮抗阿片样物质以阻断TLR4介导的胶质细胞激活。细胞分析和动物模型将用于评估TLR4拮抗剂在体外和体内对胶质细胞活化的抑制作用。该研究具有重要意义，因为它有望建立TLR4/MD-2蛋白-蛋白复合物作为预防和治疗阿片类药物滥用的新治疗靶点。就其对科学进步的积极影响而言，这项工作将(1)提高对药物依赖和疼痛抑制的科学理解，(2)允许新一代治疗方法的发展。公共卫生相关性：我们的目标是揭示阿片类药物诱导的神经胶质激活的机制，这对药物成瘾和滥用的发展起重要作用。作为拟议的研究的结果，我们期望更好地理解阿片诱导的胶质细胞激活的分子机制，并阐明调节这种激活的新靶点。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认识；(2)允许新一代疗法的发展。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Development of β-amino alcohol derivatives that inhibit Toll-like receptor 4 mediated inflammatory response as potential antiseptics.

DOI：
10.1021/jm2003365
发表时间：
2011-07-14
期刊：
JOURNAL OF MEDICINAL CHEMISTRY
影响因子：
7.3
作者：
Chavez, Sherry A.;Martinko, Alexander J.;Lau, Corinna;Pham, Michael N.;Cheng, Kui;Bevan, Douglas E.;Mollnes, Tom E.;Yin, Hang
通讯作者：
Yin, Hang

Toll-like receptor 4 in CNS pathologies.