权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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)：本提案的目标是为申请人提供一条独立的途径，成为镰状细胞病(SCD)疼痛领域的临床研究员和专家。疼痛导致SCD患者的显著发病率，目前对SCD疼痛的了解存在差距。这种知识差距阻碍了SCD疼痛新疗法的发展。因此，申请者的首要职业目标是通过致力于SCD疼痛的研究来开始弥合这一知识差距。申请者努力成为SCD疼痛方面的专家，并开发和应用SCD疼痛管理和/或预防的新干预措施。她将通过开展以患者为中心的SCD疼痛研究，并从临床、生物学和研究角度参与以疼痛培训为重点的职业发展活动，开始实现这些目标。具体地说，她将需要在疼痛神经生物学的基本概念、疼痛研究方法方面的额外培训，以及在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做的，并将由导师和威斯康星医学院的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敏化的机制及其对SCD疼痛的贡献来调查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病理性疼痛的特征时，就会发生周围敏化，这种疼痛在临床上可能表现为对机械或热刺激的高敏感性。在小鼠和SCD患者身上的初步数据显示，当处于基线健康状态时，他们都表现出对热刺激和冷刺激的过敏。在小鼠中，这种过敏性会随着缺氧-复氧而恶化，这是一种实验室诱导的方法，会导致镰状现象。目前尚不清楚SCD患者是否会出现这种敏感性恶化，这种过敏反应的潜在原因也不清楚。在非SCD模型中，包括白三烯在内的慢性炎症已被证明能敏化疼痛感受器。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增加，并且更高的水平与更频繁的疼痛相关。白三烯在SCD外周致敏中的作用尚未被研究。因此，这项建议旨在使用一种名为定量感觉测试(QST)的有效方法来进一步研究SCD患者的外周致敏作用，该方法可以安全可行地测量热(热、冷)痛阈值，并将探索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冷热痛阈值，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。这一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一个基于机制的指南，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，减轻患者的痛苦有SCD经验。