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

基本信息

批准号：
9304263
负责人：
Amanda M Brandow
金额：
$ 16.69万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-15 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9304263
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 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 Modeling Morbidity - disease rate Mus Neuraxis Neurobiology Nociceptors Pain Pain Research Pain Threshold Pain management Pathway interactions Patients Perception Peripheral Peripheral Nerves Peripheral Nervous System Phenotype Plasma Precipitating Factors Prevention Preventive measure Primary Lesion Quality of life Questionnaires Reporting Research Research Activity Role Sensory Sickle Cell Sickle Cell Anemia Site Speed Stimulus Suggestion Syndrome System 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 mortality new therapeutic target novel novel therapeutics painful neuropathy patient oriented research prevent public health relevance screening sickling somatosensory spontaneous pain training opportunity urinary

项目摘要

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）：该提案的目标是为申请人提供一条独立作为镰状细胞病（SCD）疼痛领域的临床研究者和专家的途径。疼痛导致 SCD 患者显着发病，目前对 SCD 疼痛的理解存在知识空白。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通过将她的职业生涯奉献给 SCD 疼痛的研究来开始缩小这一知识差距。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。她将通过开展以患者为中心的以 SCD 疼痛为重点的研究，并参与以临床、生物学和研究角度的疼痛培训为重点的职业发展活动，开始实现这些目标。具体来说，她将需要接受有关疼痛神经生物学基本概念、疼痛研究方法的额外培训，以及急性和慢性疼痛管理方面的进一步培训。她的职业发展计划专门针对她在儿科疼痛方面的培训需求，并将受到威斯康星医学院的导师和科学咨询委员会的指导。培训计划利用了威斯康星医学院的培训机会，也将利用机构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敏化机制及其对 SCD 疼痛的影响来研究 SCD 疼痛的基础神经生物学。当周围神经损伤或变化导致神经性疼痛的特征时，就会发生周围敏化，神经性疼痛在临床上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，在健康基线状态下，它们都表现出对热和冷刺激的过敏反应。在小鼠中，这种超敏反应会因缺氧复氧而恶化，缺氧复氧是一种实验室诱导的方法，可诱发镰状现象。目前尚不清楚这种敏感性恶化是否发生在 SCD 患者中，而且这种过敏的根本原因尚不清楚。慢性炎症，包括白三烯，已被证明可以使非 SCD 模型中的疼痛感知伤害感受器敏感。此外，与对照组相比，SCD 患者的白三烯含量升高，在急性疼痛期间进一步升高，并且较高的水平与更频繁的疼痛相关。尚未研究白三烯对 SCD 外周敏化的影响。因此，本提案旨在使用一种称为定量感觉测试 (QST) 的有效方法进一步研究 SCD 患者的外周敏感性，其中可以安全可行地测量热（热、冷）疼痛阈值，并将探讨白三烯与这种敏感性的关联。我们将使用 QST 来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。该提案的结果有可能为 SCD 疼痛的神经生物学的进一步研究提供基于机制的指导，并最终可能有助于发现预防或治疗 SCD 疼痛并减轻患者痛苦的治疗新靶点。具有SCD经验。