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
• 负责人: Hang Hubert Yin
• 金额: $ 3.79万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7778132
• 关键词: Absence of pain sensation; Address; Adverse effects; Animal Model; Arts; Attenuated; Binding; Biochemistry; Biological Assay; Biology; Cellular Assay; Chemicals; Clinical; Collaborations; Complex; Dependence; Development; Disease; Drug Addiction; Generations; Goals; In Vitro; Knowledge; Length; Letters; Ligands; Light; Link; Literature; Mediating; Membrane; Molecular; Molecular Conformation; Myelogenous; Nervous System Physiology; Neuraxis; Neurobiology; Neuroglia; Neurons; Opiate Addiction; Opiates; Opioid; Opioid Analgesics; Opioid Receptor; Outcome; Overdose; Pain; Pain management; Pathology; Pathway interactions; Peptides; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacotherapy; Proteins; Research; Role; Seeds; Sepsis; Services; Signal Pathway; Signal Transduction; Specificity; Structure; Technology; Testing; Work; addiction; assay development; clinical application; clinical efficacy; clinically relevant; design; drug development; high reward; high risk; inhibitor/antagonist; innovation; insight; molecular recognition; novel; novel therapeutics; opioid abuse; painful neuropathy; prevent; protein protein interaction; prototype; public health relevance; receptor; receptor function; scaffold; small molecule; toll-like receptor 4

DESCRIPTION (provided by applicant): The pharmacological treatment of pain has long been limited by the negative side effects of opioids: development of tolerance, dependence, and possibility of overdose. A literature has developed linking opiate side effects to their influence on glial cells of the central nervous system (CNS). Herein lies a proposal to investigate the role of an opiate-mediated glial activation, via the signaling pathway mediated by toll-like receptor 4 (TLR4). TLR4, an integral membrane receptor expressed in glia but no in neurons within the CNS, functions in complex with its accessory protein, Myeloid Differentiation protein-2 (MD-2). The TLR4/MD-2 complex is crucial to the TLR4-signaling transduction. The proposal's central hypothesis is that inhibition of the TLR4/MD-2 association will impede the TLR4-signaling pathway, thereby preventing the negative side effects from opiate-induced glial activation. By selectively blocking the critical protein-protein interactions between TLR4 and MD-2, opiate tolerance and dependence is predicted to attenuate, thereby increasing the efficacy of current pain pharmacotherapies. This approach is innovative, as it is the first proposal aimed at the inhibition of glial- mediated opioid side effects. Further, the research is expected to yield significant outcomes: (1) inhibitors of the TLR4/MD-2 interaction will be prototypes for the development of drugs to counteract opioid side effects from tolerance to addiction and overdose. The TLR4/MD-2 interaction is also implicated in other pathologies (e.g. sepsis), and will therefore serve potential targets for various diseases. (2) Importantly, antagonists of the TLR4/MD-2 interaction will elucidate the contribution of the TLR4 pathway to opiate-induced glial activation. The inhibitors will help determine the mechanism of action of the TLR4 pathway itself, shedding light on the molecular specificity with which TLR4 recognizes its ligands. The proposed studies are built on a strong collaborative team with a spectrum of expertise covering from protein design, biochemistry and biophysical assay development, x-ray structural analysis, and animal models for pain management. The proposed studies employ computationally designed peptides derived from the TLR4-bidning regions of MD-2, which is expected to compete with the full-length MD-2 protein and prevent the TLR4 signal transduction. These peptides will provide starting points for the small-molecule inhibitors. The significance of this work lies in its impacts on both clinical and scientific advancement. Dissecting the mechanism of opiate-induced glial activation will help us understand the development of opioid tolerance and addiction, as well as establish a novel angle from which to address drug dependence and abusing of these opiates. Regarding its impact on scientific advancement, the proposed studies will illuminate the molecular mechanism of TLR4 activation, which is relevant to a many interrelated signaling and immunomodulatory pathways, and crucial to the understanding of pain suppression. PUBLIC HEALTH RELEVANCE: The proposed research aims to unravel the mechanism of opioid-induced glial activation that both hinders the ability of opioids to effectively control pain and also importantly contributes to the development of drug addiction and abuse. State-of-the-art technologies will be employed to define, design, create, and test new chemical entities predicted to prevent opioid induced glial activation, thereby optimizing opioid analgesia while preventing negative consequences of clinical opioid use.

描述（由申请人提供）：长期以来，疼痛的药物治疗一直受到阿片类药物副作用的限制：耐受性，依赖性和过量的可能性。文献已经发展了阿片类药物的副作用与其对中枢神经系统（CNS）胶质细胞的影响。因此，我们建议通过toll样受体4 （TLR4）介导的信号通路来研究阿片类药物介导的胶质细胞激活的作用。TLR4是一种完整的膜受体，在神经胶质细胞中表达，而在中枢神经系统内的神经元中不表达，它与其附属蛋白髓样分化蛋白-2 （MD-2）复合起作用。TLR4/MD-2复合物对TLR4信号转导至关重要。该提案的中心假设是，抑制TLR4/MD-2关联将阻碍TLR4信号通路，从而防止阿片类诱导的胶质细胞激活的负面副作用。通过选择性阻断TLR4和MD-2之间关键的蛋白-蛋白相互作用，阿片耐受性和依赖性预计会减弱，从而提高当前疼痛药物治疗的疗效。这种方法是创新的，因为它是第一个旨在抑制胶质介导的阿片副作用的建议。此外，该研究有望取得重大成果：(1)TLR4/MD-2相互作用抑制剂将成为开发药物的原型，以对抗阿片类药物从耐受性到成瘾和过量的副作用。TLR4/MD-2相互作用也涉及其他病理（如败血症），因此将成为各种疾病的潜在靶点。(2)重要的是，TLR4/MD-2相互作用的拮抗剂将阐明TLR4途径在阿片诱导的胶质细胞激活中的作用。这些抑制剂将有助于确定TLR4途径本身的作用机制，揭示TLR4识别其配体的分子特异性。拟议的研究建立在一个强大的合作团队的基础上，该团队拥有涵盖蛋白质设计，生物化学和生物物理分析开发，x射线结构分析和疼痛管理动物模型的专业知识。本研究采用计算设计的从MD-2的TLR4结合区域衍生的多肽，有望与全长MD-2蛋白竞争并阻止TLR4信号转导。这些肽将为小分子抑制剂提供起点。这项工作的意义在于它对临床和科学进步的影响。剖析阿片类药物诱导的神经胶质活化机制有助于我们理解阿片类药物耐受和成瘾的发展，并为解决阿片类药物依赖和滥用问题建立一个新的视角。就其对科学进步的影响而言，所提出的研究将阐明TLR4激活的分子机制，这与许多相互关联的信号传导和免疫调节途径有关，对理解疼痛抑制至关重要。