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

外周敏化作为镰状细胞病疼痛的新机制

• 批准号: 8580484
• 负责人: Amanda M Brandow
• 金额: $ 13.93万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8580484
• 关键词: Ache; Acute; Acute Pain; Admission activity; Adult; Advisory Committees; Affect; Afferent Neurons; African American; Age; Caring; Characteristics; Childhood; Chronic; Clinical; Clinical Investigator; Data; Descriptor; Development; Development Plans; Disease model; Environmental Wind; Esthesia; Event; Exhibits; Frequencies; Functional disorder; Goals; Health; Heating; Hospitals; Hour; Human; Hypersensitivity; Hypoxia; Inflammation; Inflammation Mediators; Inflammatory; Institution; Intervention; Investigation; Knowledge; Laboratories; Lead; Leukotriene B4; Leukotrienes; Measurement; Measures; Mechanics; Medical; Mentors; Methodology; Methods; Morbidity - disease rate; Mus; Neuraxis; Neurobiology; Nociceptors; Pain; Pain Research; Pain Threshold; Pain management; Pathway interactions; Patients; Perception; Peripheral; Peripheral Nerves; Peripheral Nervous System; Plasma; Precipitating Factors; Prevention; Primary Lesion; Quality of life; Reporting; Research; Research Activity; Role; Sensory; Sickle Cell; Sickle Cell Anemia; Site; Speed; Stimulus; Suggestion; Tactile; Testing; Touch sensation; Training; Urine; Wisconsin; barometric pressure; base; biological research; career; career development; chronic pain; cold temperature; cysteinyl-leukotriene; experience; heat stimulus; medical schools; new therapeutic target; novel; painful neuropathy; patient oriented research; prevent; public health relevance; screening; sickling; somatosensory; spontaneous pain; urinary

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.

描述（由申请人提供）：该提案的目的是为申请人提供独立途径，成为镰状细胞病（SCD）疼痛领域的临床研究者和专家。疼痛对SCD患者引起了明显的发病率，目前了解SCD疼痛的知识存在差距。这种知识差距阻碍了SCD疼痛的新疗法的发展。因此，申请人的总体职业目标是通过将她的职业献给SCD疼痛的研究来开始缩小这一知识差距。申请人致力于成为SCD疼痛的专家，并开发和应用新颖的干预措施，以进行SCD疼痛管理和/或预防。她将开始通过进行以患者为目标的研究来实现这些目标，这些研究专注于SCD疼痛，并从事临床，生物学和研究角度培训培训的职业发展活动。具体而言，她将需要在疼痛神经生物学的基本概念，疼痛研究方法以及在管理急性和慢性疼痛方面的进一步培训方面需要进行其他培训。她的职业发展计划是针对她在儿科疼痛方面的培训需求量身定制的，将由威斯康星州医学院的导师和科学咨询委员会指导。培训计划利用威斯康星州医学院的培训机会，还将利用机构以外的机会来补充她现场疼痛训练。研究活动将包括通过探索外周敏化机制及其对SCD疼痛的贡献来研究SCD疼痛的潜在神经生物学。当周围神经的损害或变化导致神经性疼痛的特征时，周围敏化会发生，从而在临床上表现为对机械或热刺激的高敏性。小鼠和SCD患者的初步数据表明，在健康状况下，它们都表现出对热量和冷刺激的超敏反应。在小鼠中，这种超敏反应会因低氧抗活化而恶化，这是一种实验室诱导的方法，可诱导恶心现象。尚不清楚SCD患者是否会发生这种恶化的敏感性，而这种过敏性的根本原因尚不清楚。慢性炎症（包括白细胞）已被证明可以使非SCD模型中的疼痛感受伤害感受器敏感。此外，与对照组相比，SCD患者的白三烯已显示出升高，在急性疼痛期间进一步增加，并且更高的水平与更频繁的疼痛有关。尚未研究白细胞对SCD外周敏化的贡献。因此，该提案旨在使用经过验证的方法论（QST）进一步研究人类的外围敏化（QST），在该方法中，热（热，冷）疼痛阈值可以安全，可行地测量，并将探索白细胞与这种敏感性的关联。我们将使用QST评估急性疼痛事件中的热和冷痛阈值，并确定白三烯水平与基线和疼痛期间这些热疼痛阈值的关系。该提案的结果有可能提供基于机械的指南，以进一步研究SCD疼痛的神经生物学，最终可能有助于发现用于预防或治疗SCD疼痛并缓解患者痛苦的新型治疗靶标的新靶标。 具有SCD经验。