NOS1AP as a novel target for treating pathological pain

NOS1AP作为治疗病理性疼痛的新靶点

• 批准号: 9204399
• 负责人: Michael Courtney
• 金额: $ 28.19万
• 依托单位: TRUSTEES OF INDIANA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-08 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9204399
• 关键词: Adaptor Signaling Protein; Adverse effects; Analgesics; Attenuated; Biochemical; Biological Assay; Cells; Clinical; Cognition; Complex; Development; Disease; Dose; Enzymes; Event; Exhibits; Future; Generations; Glutamates; Goals; Human; Hypersensitivity; Laboratories; Life; Lumbar spinal cord structure; Maintenance; Mediating; Medical; Memory; Mitogen-Activated Protein Kinases; Modeling; Motor; N-Methyl-D-Aspartate Receptors; NMDA receptor antagonist; Neuraxis; Neurons; Neuropathy; Nitric Oxide; Nitric Oxide Pathway; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Nociception; Paclitaxel; Pain; Pain management; Pathologic; Pathologic Processes; Peptides; Peripheral Nervous System Diseases; Pharmacotherapy; Physiological; Physiological Processes; Play; Production; Productivity; Proteins; Quality of life; Rattus; Receptor Activation; Receptor Signaling; Recruitment Activity; Role; Savings; Scaffolding Protein; Signal Pathway; Signal Transduction; Testing; Therapeutic; Therapeutic Intervention; Therapeutic Uses; Treatment Efficacy; attenuation; base; cancer therapy; central sensitization; chemokine; chemotherapeutic agent; chemotherapy; chemotherapy induced neuropathy; chronic pain; conventional therapy; cost; cytokine; drug development; drug discovery; excitotoxicity; experimental study; glutamatergic signaling; inhibitor/antagonist; mRNA Expression; nervous system disorder; novel; pain behavior; painful neuropathy; postsynaptic density protein; presynaptic density protein 95; prevent; protein protein interaction; public health relevance; receptor; receptor function; response; scaffold; small molecule; small molecule inhibitor; socioeconomics; therapeutic target; tool

 DESCRIPTION (provided by applicant): Chemotheraphy-induced peripheral neuropathy (CIPN) limits life saving anti-cancer treatment, can be permanent and negatively impacts quality of life. It is thus important to dissect the critical signaling pathways involved in development an maintenance of CIPN and identify therapeutic strategies to prevent or treat CIPN. The NMDA receptor (NMDAR) signaling complex plays a key role in central sensitization of chronic pain. While NMDAR antagonists are efficacious in decreasing pain sensitization, they have limited therapeutic uses because they disrupt normal physiological processes (e.g. motor function, memory and cognition). The NMDAR signaling complex consists of many protein partners including the scaffold postsynaptic density 95 kDA (PSD95) protein, the neuronal enzyme nitric oxide synthase (nNOS) and its adaptor protein NOS1AP. Disruption of specific steps downstream of NMDAR activation offers the opportunity to decrease pain sensitization while avoiding some of the broader side effects associated with upstream receptor blockade. Our preliminary studies suggest that the interface between nNOS and NOS1AP represents a previously unrecognized candidate target for the development of new analgesics for CIPN. Aim 1 will determine whether disruption of nNOS interactions with its upstream or downstream protein partners bias NMDAR signaling in a functionally selective manner using biochemical and cell based assays. Aim 2 will evaluate the therapeutic potential of disrupting the nNOS-NOS1AP protein-protein interface for suppressing neuropathic pain induced by the chemotherapeutic agent paclitaxel and correlate antinociceptive efficacy of intrathecally administered agents with disruption of the nNOS-NOS1AP complex in lumbar spinal cord of paclitaxel-treated rats. Aim 3 will identify signaling pathways downstream of NOS1AP that underly the ability of nNOS-NOS1AP inhibitors to attenuate paclitaxel-induced neuropathic pain. In this project, the mechanism by which peptide and small molecule protein-protein interaction inhibitors to selectively block NMDAR-induced hypersensitivity in a paclitaxel-induced neuropathic pain model will be elucidated. If confirmed, a new generation of modulators of pathological pain could be developed by targeting this interaction.

 描述（由申请人提供）：化疗诱导的周围神经病变（CIPN）限制了挽救生命的抗癌治疗，可能是永久性的，并对生活质量产生负面影响。因此，重要的是要剖析参与发展和维持CIPN的关键信号通路，并确定治疗策略，以预防或治疗CIPN。NMDA受体（NMDAR）信号复合物在慢性疼痛的中枢致敏中起关键作用。虽然NMDAR拮抗剂在降低疼痛敏感性方面是有效的，但是它们具有有限的治疗用途，因为它们破坏正常的生理过程（例如运动功能、记忆和认知）。NMDAR信号复合物由许多蛋白质伴侣组成，包括支架突触后密度95 kDA（PSD 95）蛋白，神经元酶一氧化氮合酶（nNOS）及其衔接蛋白NOS 1AP。破坏NMDAR激活下游的特定步骤提供了降低疼痛敏感性的机会，同时避免了与上游受体阻断相关的一些更广泛的副作用。我们的初步研究表明，nNOS和NOS 1AP之间的接口代表了一个以前未被认识到的候选目标，为CIPN开发新的镇痛药。目的1将使用生物化学和基于细胞的测定来确定nNOS与其上游或下游蛋白质伴侣的相互作用的破坏是否以功能选择性方式使NMDAR信号传导偏置。目的2将评估破坏nNOS-NOS 1AP蛋白-蛋白界面以抑制由化疗剂紫杉醇诱导的神经病理性疼痛的治疗潜力，并将鞘内给药的药剂的抗伤害感受功效与紫杉醇治疗的大鼠的腰髓中nNOS-NOS 1AP复合物的破坏相关联。目的3将确定nNOS-NOS 1AP抑制剂减弱紫杉醇诱导的神经病理性疼痛的能力的NOS 1AP下游的信号通路。在本项目中，将阐明肽和小分子蛋白质-蛋白质相互作用抑制剂在紫杉醇诱导的神经性疼痛模型中选择性阻断NMDAR诱导的超敏反应的机制。如果得到证实，可以通过靶向这种相互作用开发新一代病理性疼痛调节剂。