Peripheral Sensitization as a Novel Mechanism for Pain in Sickle Cell Disease

描述（由申请人提供）：本申请的目标是为申请人提供一条途径，使其成为镰状细胞病（SCD）疼痛领域的独立临床研究者和专家。疼痛是SCD患者的重要致病因素，目前对SCD疼痛的认识还存在空白。这种知识差距阻碍了SCD疼痛新疗法的发展。因此，申请人的首要职业目标是通过将自己的职业生涯奉献给SCD疼痛的研究来缩小这一知识差距。申请人努力成为SCD疼痛方面的专家，并开发和应用新的干预措施来管理和/或预防SCD疼痛。她将开始通过执行以患者为导向的研究，专注于SCD疼痛和从事职业发展活动，专注于从临床，生物学和研究角度培训疼痛来实现这些目标。具体来说，她将需要在疼痛神经生物学的基本概念、疼痛研究方法以及急性和慢性疼痛管理方面的进一步培训。她的职业发展计划是专门为她在儿科疼痛方面的培训需求量身定制的，并将由威斯康星医学院的导师和科学咨询委员会指导。该培训计划利用了威斯康星医学院的培训机会，也将利用该机构以外的机会来补充她的现场疼痛培训。研究活动将包括通过探索外周致敏机制及其对SCD疼痛的贡献来研究SCD疼痛的潜在神经生物学。当周围神经的损伤或改变导致神经性疼痛的特征时，就会发生外周致敏，这种疼痛在临床上可以表现为对机械或热刺激的超敏反应。SCD小鼠和患者的初步数据显示，在基线健康状态下，它们都表现出对热和冷刺激的超敏反应。在小鼠中，这种超敏反应随着缺氧再氧化而恶化，这是一种实验室诱导的方法，可诱导镰状细胞现象。目前尚不清楚SCD患者是否会出现这种恶化的敏感性，也不清楚这种超敏反应的根本原因。慢性炎症，包括白三烯，已被证明在非scd模型中使痛觉伤害感受器敏感。此外，与对照组相比，白三烯在SCD患者中升高，在急性疼痛期间进一步增加，更高的水平与更频繁的疼痛有关。白三烯对SCD外周致敏的作用尚未研究。因此，本提案旨在使用一种被称为定量感觉测试（QST）的有效方法进一步研究SCD患者的外周致敏性，其中热（热，冷）痛阈值可以安全可行地测量，并将探索白三烯与这种敏感性的关系。我们将使用QST来评估急性疼痛事件中的热痛阈值和冷痛阈值，并确定白三烯水平与基线和疼痛期间这些热痛阈值的关系。该建议的结果有可能为进一步研究SCD疼痛的神经生物学提供基于机械的指导，并最终可能有助于发现新的治疗靶点，以预防或治疗SCD疼痛并减轻患者的痛苦

DESCRIPTION (provided by applicant): The goal of this proposal is to provide the applicant a pathway to independence as a clinical investigator and expert in the field of pain in sickle cell disease (SCD). Pain causes significant morbidity for patients with SCD and currently there is a gap in knowledge in the understanding of SCD pain. This knowledge gap has hindered the development of new treatments for SCD pain. Thus, the overarching career goals of the applicant are to begin to close this knowledge gap by dedicating her career to the study of SCD pain. The applicant strives to become an expert in SCD pain and to develop and apply novel interventions for SCD pain management and/or prevention. She will begin to achieve these goals by performing patient-oriented research focused on SCD pain and engaging in career development activities focused on training in pain from clinical, biological, and research perspectives. Specifically, she will require additional training in the fundamental concepts of pain neurobiology, methodology of pain research, and further training in the management of both acute and chronic pain. Her career development plan is specifically tailored to her training needs in pediatric pain and will be guided by mentors and a scientific advisory committee at the Medical College of Wisconsin. The training plan takes advantage of training opportunities at the Medical College of Wisconsin and will also take advantage of opportunities outside of the institution to supplement her on-site pain training. The research activities will include investigation into the underlying neurobiology of SCD pain by exploration into mechanisms of peripheral sensitization and its contribution to SCD pain. Peripheral sensitization occurs when damage to or change in peripheral nerves result in features of neuropathic pain which can clinically present as hypersensitivity to mechanical or thermal stimuli. Preliminary data in both mice and patients with SCD reveal they both display hypersensitivity to heat and cold stimuli when in baseline state of health. In mice, this hypersensitivity worsens with hypoxia-reoxygenation, a laboratory-induced method that induces sickling phenomenon. It is not known whether this worsening sensitivity occurs in patients with SCD and the underlying reason for this hypersensitivity is not known. Chronic inflammation, including leukotrienes, has been shown to sensitize pain sensing nociceptors in non-SCD models. In addition, leukotrienes have been shown to be elevated in SCD patients compared to controls, increase further during acute pain, and higher levels have been associated with more frequent pain. The contribution of leukotrienes to peripheral sensitization in SCD has not been studied. Thus, this proposal aims to further study peripheral sensitization in humans with SCD using a validated methodology called quantitative sensory testing (QST) where thermal (heat, cold) pain thresholds can be safely and feasibly measured and will explore the association of leukotrienes with this sensitivity. We will use QST to evaluate heat and cold pain thresholds during an acute pain event and determine the relationship of leukotriene levels to these thermal pain thresholds at baseline and during pain. Results of this proposal have the potential to provide a mechanistic-based guide for further studies into the neurobiology of SCD pain and ultimately may contribute to the discovery of novel targets for therapeutics to prevent or treat SCD pain and relieve the suffering that patients with SCD experience.