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

描述（由申请人提供）：本提案的目标是为申请人提供一条独立的途径，使其成为镰状细胞病（SCD）疼痛领域的临床研究者和专家。疼痛导致SCD患者的显著发病率，目前在对SCD疼痛的理解方面存在知识差距。这种知识差距阻碍了SCD疼痛新疗法的开发。因此，申请人的总体职业目标是开始通过致力于SCD疼痛的研究来缩小这一知识差距。申请人努力成为SCD疼痛专家，并开发和应用用于SCD疼痛管理和/或预防的新型干预措施。她将开始通过进行以患者为导向的研究，重点是SCD疼痛和从事职业发展活动，重点是从临床，生物学和研究角度的疼痛培训，以实现这些目标。具体来说，她将需要在疼痛神经生物学的基本概念，疼痛研究的方法，并在急性和慢性疼痛的管理进一步培训的额外培训。她的职业发展计划是专门针对她在儿科疼痛的培训需求，并将指导导师和科学咨询委员会在威斯康星州医学院。该培训计划利用了威斯康星州医学院的培训机会，也将利用机构以外的机会，以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。当外周神经的损伤或变化导致神经性疼痛的特征时，发生外周致敏，神经性疼痛在临床上可表现为对机械或热刺激的超敏反应。小鼠和SCD患者的初步数据显示，当处于基线健康状态时，它们都对热和冷刺激表现出超敏反应。在小鼠中，这种超敏反应与缺氧-复氧有关，缺氧-复氧是一种诱导镰状现象的实验室诱导方法。尚不清楚SCD患者是否会发生这种敏感性恶化，也不清楚这种超敏反应的根本原因。慢性炎症，包括白三烯，已显示在非SCD模型中使疼痛感测伤害感受器敏感。此外，与对照组相比，SCD患者的白三烯水平升高，在急性疼痛期间进一步升高，并且更高的水平与更频繁的疼痛相关。尚未研究白三烯对SCD外周致敏的作用。因此，本提案旨在使用称为定量感觉测试（QST）的经验证方法进一步研究SCD患者的外周致敏作用，其中可以安全可行地测量热（热，冷）疼痛阈值，并将探索白三烯与这种敏感性的相关性。我们将使用QST评估急性疼痛事件期间的热痛阈值和冷痛阈值，并确定基线和疼痛期间白三烯水平与这些热痛阈值的关系。这一提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制的指导，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。 有SCD经验。

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.