Role of TRPV1 in Cancer Pain

描述（由申请人提供）：研究培训计划的长期目标是作为Meeghan Lautner博士的临床科学家发展关键和综合研究技能的培训工具。采用临床研究（MSCI）中的结构化MS程序作为正式培训工具，拟议的研究计划将测试肿瘤细胞释放可激活或致敏辣椒素受体TRPV1的可溶性因子的假设。TRPV1在痛觉感受器的一个主要亚类上表达，似乎在许多疼痛状态中起关键作用。虽然已经提出了几种肿瘤诱导疼痛的机制，但所提出的假设提供了一种涉及瞬时受体亚型V1 （TRPV1）激活的新机制。如果产生的数据支持这一假设，那么全新的治疗干预措施可能会被开发出来，用于治疗癌症疼痛。这个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是一个值得关注的领域，这是许多患者公认的主要临床问题（Mantyh 2006； Loscalzo等人2007；Macvean等人2007）。迄今为止产生的初步数据有力地支持了可溶性因子的释放，该因子通过TRPV1触发培养的感觉神经元释放CGRP，拮抗剂I-RTX的阻断表明了这一点。第一个具体目标是通过细胞信号（细胞内钙积累，[Ca]i）和功能（降钙素基因相关肽，CGRP释放）测定，确定ATTC肿瘤细胞系是否释放一种激活或致敏TRPV1的可溶性因子。第二个目的是确定在手术切除过程中收集的患者肿瘤是否释放一种激活或致敏TRPV1的可溶性因子，以及与不释放TRPV1调节因子的其他患者的肿瘤相比，释放这种可溶性化合物的肿瘤是否与患者报告更大的疼痛强度有关。公共卫生相关性：尽管在过去几十年中取得了相当大的进步，但癌痛仍然是许多患者的主要问题。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。

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.