Role of TRPV1 in Cancer Pain

TRPV1 在癌痛中的作用

• 批准号: 7544656
• 负责人: Meeghan Ann Lautner
• 金额: $ 4.96万
• 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 2010-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7544656
• 关键词: Afferent Neurons; Area; Biological Assay; CALCA gene; Calcitonin Gene-Related Peptide; Calcium; Cancer Pain Management; Capsaicin; Class; Clinical; Clinical Trials; Conditioned Culture Media; Data; Development; Future; Knockout Mice; Malignant Neoplasms; Mediating; Medical; Nociceptors; Operative Surgical Procedures; Pain; Patients; Peripheral; Procedures; Public Health; Reporting; Research; Research Project Grants; Research Training; Role; S100A12 gene; Scientist; Signal Transduction; Structure; Testing; Therapeutic Intervention; Training; Tumor Cell Line; V1 Receptors; cancer pain; capsaicin receptor; human S100A12 protein; neoplastic cell; novel; novel therapeutics; programs; 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(由申请者提供)：研究培训计划的长期目标是作为Meeghan Lautner博士的临床科学家发展关键和综合研究技能的培训工具。使用临床研究中的结构化MS计划(MSCI)作为正式培训工具，拟议的研究计划将测试肿瘤细胞释放一种激活或敏化辣椒素受体TRPV1的可溶性因子的假设。TRPV1在伤害性感受器的一个主要亚类上表达，似乎在许多疼痛状态中起着关键作用。虽然已经提出了几种肿瘤诱导疼痛的机制，但提出的假说提供了一种新的机制，涉及到瞬时受体亚型V1(TRPV1)的激活。如果产生的数据支持这一假设，那么可能会开发出全新的治疗措施来管理癌症疼痛。该项目具有明确的医学和科学意义。尽管几十年来在治疗多种形式的癌症方面取得了成功，但与癌症相关的疼痛仍然受到关注，这是许多患者公认的主要临床问题(Mantyh 2006；Loscalzo等人)。2007年；Macvean等人。2007)。到目前为止产生的初步数据为通过TRPV1从培养的感觉神经元释放触发CGRP释放的可溶性因子提供了强有力的支持，拮抗剂I-RTX表明这一点。第一个特定目标将确定ATTC肿瘤细胞系是否释放一种可溶性因子，通过对培养的感觉神经元进行细胞信号(细胞内钙积累，[Ca]i)和功能(降钙素基因相关肽，CGRP释放)分析来激活或敏化TRPV1。第二个目标将确定在手术去体积过程中从患者身上收集的肿瘤是否会释放一种激活或敏化TRPV1的可溶性因子，以及与从其他患者收集的不释放TRPV1调节因子的肿瘤相比，释放这种可溶性化合物的肿瘤是否与报告更强疼痛强度的患者有关。公共卫生相关性：尽管在过去的几十年里取得了长足的进步，但癌症疼痛仍然是许多患者面临的一个主要问题。该项目将评估辣椒素受体TRPV1是否与癌症疼痛有关。如果是这样，那么新型止痛药可能对未来的患者有价值。