Role of TRPV1 in Cancer Pain

TRPV1 在癌痛中的作用

• 批准号: 7743735
• 负责人: Meeghan Ann Lautner
• 金额: $ 4.27万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7743735
• 关键词: Afferent Neurons; Analgesics; Area; Biological Assay; Calcitonin Gene-Related Peptide; Calcium; Cancer Pain Management; Capsaicin; Clinical; Clinical Trials; Conditioned Culture Media; Data; Development; Future; Knockout Mice; Malignant Neoplasms; Mediating; Medical; Nociceptors; Operative Surgical Procedures; Pain; Patients; Peripheral; Procedures; Reporting; Research; Research Project Grants; Research Training; Role; Scientist; Signal Transduction; Structure; Testing; Training; Tumor Cell Line; V1 Receptors; cancer pain; capsaicin receptor; neoplastic cell; novel; novel therapeutic intervention; programs; public health relevance; receptor; skills; success; tumor

DESCRIPTION (provided by applicant): The long term objectives of the research training plan is to serve as a training vehicle for the development of critical and comprehensive research skills as a clinician scientist for Dr. Meeghan Lautner. Using a structured MS program in Clinical Investigation (MSCI) as a formal training vehicle, the proposed research plan will test the hypothesis that tumor cells release a soluble factor that activates or sensitizes the capsaicin receptor TRPV1. TRPV1 is expressed on a major subclass of nociceptors and appears to be pivotally involved in many pain states. Although several mechanisms for tumor-induced pain have been proposed, the proposed hypothesis provides a novel mechanism involving activation of the transient receptor subtype V1 (TRPV1). If the data generated supports this hypothesis, then completely new therapeutic interventions may be developed for the management of cancer pain. This project has clear medical and scientific implications. Despite decades of success in treating many forms of cancer, a continuing area of concern is pain associated with cancer, which is a well recognized major clinical problem for many patients (Mantyh 2006; Loscalzo et al. 2007; Macvean et al. 2007). Preliminary data generated to date provide strong support for the release of a soluble factor which triggers CGRP release from cultured sensory neurons via TRPV1, as indicated by blockade with the antagonist I-RTX. The first specific aim will determine whether ATTC tumor cell lines release a soluble factor that activates or sensitizes TRPV1 using both cell signaling (intracellular calcium accumulation, [Ca]i) and functional (calcitonin gene-related peptide, CGRP release) assays on cultured sensory neurons. The second aim will determine whether tumors collected during surgical de-bulking procedures from patients release a soluble factor that activates or sensitizes TRPV1 and whether tumors that release this soluble compound are associated with patients reporting greater pain intensities compared with tumors collected from other patients that do not release a TRPV1 modulating factor. PUBLIC HEALTH RELEVANCE: Despite considerable advances over the last several decades, cancer pain represents a major problem in many patients. This project will evaluate whether the capsaicin receptor, TRPV1, contributes to cancer pain. If so, then new types of pain killers might be of value to future patients.

描述（由申请人提供）：研究培训计划的长期目标是作为Meeghan Lautner博士临床科学家发展关键和综合研究技能的培训工具。使用临床研究（MSCI）中的结构化MS程序作为正式的培训工具，拟议的研究计划将测试肿瘤细胞释放激活或敏化辣椒素受体TRPV 1的可溶性因子的假设。TRPV 1在伤害感受器的主要亚类上表达，并且似乎枢转地参与许多疼痛状态。虽然已经提出了几种肿瘤引起疼痛的机制，但所提出的假说提供了一种涉及瞬时受体亚型V1（TRPV 1）激活的新机制。如果生成的数据支持这一假设，那么可以开发全新的治疗干预措施来管理癌症疼痛。该项目具有明确的医学和科学意义。尽管数十年来在治疗多种形式的癌症方面取得了成功，但癌症相关疼痛仍是一个持续关注的领域，这是许多患者公认的主要临床问题（Mantyh 2006; Loscalzo et al. 2007; Macvean et al. 2007）。迄今为止产生的初步数据提供了强有力的支持，释放的可溶性因子，触发CGRP释放从培养的感觉神经元通过TRPV 1，如所示的阻断与拮抗剂I-RTX。第一个具体目标将使用对培养的感觉神经元的细胞信号传导（细胞内钙积累，[Ca]i）和功能（降钙素基因相关肽，CGRP释放）测定来确定ATTC肿瘤细胞系是否释放激活或致敏TRPV 1的可溶性因子。第二个目标将确定在手术减积过程中从患者收集的肿瘤是否释放激活或致敏TRPV 1的可溶性因子，以及与从其他不释放TRPV 1调节因子的患者收集的肿瘤相比，释放这种可溶性化合物的肿瘤是否与报告更大疼痛强度的患者相关。公共卫生相关性：尽管在过去几十年中取得了相当大的进展，但癌症疼痛仍然是许多患者的主要问题。该项目将评估辣椒素受体TRPV 1是否有助于癌症疼痛。如果是这样，那么新型止痛药可能对未来的患者有价值。