Biomechanical Pathways Associated with Osteoarthritis Pain

项目摘要 候选人：雷切尔·E·米勒，博士，拉什大学医学(风湿科)助理教授 伊利诺伊州芝加哥大学医学中心。米勒博士正在寻找一位有指导的研究科学家发展 获奖以获得神经生物学和生理学实验室技术方面的额外培训 她将制定一项独立的研究计划，重点是更好地了解机械生理学 骨性关节炎疼痛。具体地说，米勒博士将接受电生理学和钙信号技术方面的培训， 以及应用定制机械加载的培训。因此，这个职业发展奖将 通过为她提供必要的额外专业知识来补充她的研究生和博士后培训 建立独立的研究项目：肌肉骨骼生物学、生物力学、神经科学和 生理学。这项研究有望为研究导致心肌梗死的信号通路提供新的见解。 与异常机械负荷相关的疼痛，最终可能转化为改善 治疗骨性关节炎。这项奖励将使她能够将75%的全时当量投入到拟议的培训和科学中。在……里面 除了科学培训外，她还将受益于出席研讨会和在科学研讨会上发表演讲。 会议，负责任的研究行为培训，以及手稿写作和培训 大权在握。 环境：米勒博士最近接受了拉什大学系助理教授的职位 风湿科内科。拉什关节炎和骨科研究所，由 整形外科，解剖学和细胞生物学，风湿病和生物化学系，提供学术 翻译研究社区，结合了优秀的基础和临床研究，用于研究 骨性关节炎。此外，距离西北医学院很近，便于密切合作 神经科学和生理学方面的专家。最后，分子系的教职员工 拉什的生物物理学和生理学在包括功能在内的各种领域都有活跃的研究计划 他们的经验将有助于米勒博士提出的研究。Dr。 米勒得到了风湿科的全力支持，风湿科保证米勒博士将有 在本奖项的整个期限内，K01相关研究和培训的时间保护超过75%， 为了实现此应用程序的目标，她将拥有最少的管理、委员会和讲课 义务。她将获得所有教员的专业知识、指导、实验室空间和设备， 以及帮助她实现成为独立人士的目标所需的职业发展资源 研究员。 研究：这项建议侧重于提高对负重活动导致疼痛的理解 骨性关节炎。膝关节骨关节炎(OA)是一种疼痛的疾病，其特征是进行性损害和 所有关节组织的重塑。反常机械力在推动经济发展中发挥着重要作用 膝盖骨关节炎。在负重活动中，包括步行和爬楼梯，受损区域是 承受更大的震源应力，导致更大的破坏。同样的负重活动是 与骨性关节炎的疼痛有关。感觉神经的慢性刺激，如在骨性关节炎中，可能会导致敏感化 和慢性疼痛。因此，治疗与机械输入相关的早期OA疼痛可能对 预防慢性疼痛。我们的假设是膝关节内的异常机械力，已知为 促进关节损伤，也促进疼痛。我们认为，与活动相关的疼痛可能通过直接 机械刺激周围神经末梢或通过以下方式二次产生前痛分子 其他关节组织(包括软骨，它是神经性的)。这一假设将通过 目的1：评价关节组织内周围感觉神经末梢对 小鼠内侧半月板失稳后的机械刺激；目标2：确定 机械刺激可诱导软骨细胞产生致痛分子；目标3：识别离子类别 通过软骨细胞表达的通道和评估机械功能。

Project Summary Candidate: Rachel E. Miller, PhD is an Assistant Professor of Medicine (Division of Rheumatology) at Rush University Medical Center, Chicago, IL. Dr. Miller is seeking a Mentored Research Scientist Development Award in order to obtain additional training in neurobiology and physiology laboratory techniques necessary for her to develop an independent research program focused on better understanding the mechanophysiology of OA pain. Specifically, Dr. Miller will receive training in electrophysiology and calcium signaling techniques, as well as training in applying custom-built mechanical loading. Therefore, this career development award will complement her graduate and postdoctoral training by providing her with the additional expertise necessary for forging an independent research program bridging: musculoskeletal biology, biomechanics, neuroscience, and physiology. This research is expected to provide novel insights into the signaling pathways responsible for the pain associated with aberrant mechanical loading, which could ultimately be translated into improved therapeutics for OA. This award would enable her to devote 75% FTE to the training and science proposed. In addition to scientific training, she will benefit from attendance and presentation in seminars and scientific meetings, training in the responsible conduct of research, and training in manuscript writing and grantsmanship. Environment: Dr. Miller recently accepted an Assistant Professor position at Rush University in the Department of Internal Medicine, Division of Rheumatology. The Rush Arthritis and Orthopedics Institute, comprising the Departments of Orthopedics, Anatomy & Cell Biology, Rheumatology, and Biochemistry, provides an academic translational research community that combines excellent basic and clinical research for the study of osteoarthritis. In addition, the close proximity to Northwestern Medical Campus allows for close collaboration with experts in neuroscience and physiology. Finally, faculty members in the Department of Molecular Biophysics and Physiology at Rush have active research programs in a variety of areas including the functions of cell membranes and ion channels, and whose experience will benefit Dr. Miller's proposed research. Dr. Miller has the full support of the Division of Rheumatology and the Division guarantees that Dr. Miller will have more than 75% time protected for K01-related research and training throughout the term of this award, and, to pursue the objectives of this application, she will have minimal administrative, committee, and lecturing obligations. She will have access to all of the faculty expertise, mentorship, laboratory space and equipment, and career development resources necessary to help her to reach her goal of becoming an independent researcher. Research: This proposal focuses on improving the understanding of why weight-bearing activity causes pain in osteoarthritis. Osteoarthritis (OA) of the knee is a painful disease, characterized by progressive damage and remodeling of all joint tissues. Abnormal mechanical forces play an important role in driving the development of knee OA. During weight-bearing activities, including walking and climbing stairs, the damaged area is subjected to increased focal stresses, leading to more damage. The same weight-bearing activities are associated with pain in OA. Chronic stimulation of sensory nerves, such as in OA, may lead to sensitization and chronic pain. Therefore, treating early OA pain associated with mechanical input may be important for preventing chronic pain. Our hypothesis is that aberrant mechanical forces within the knee joint, known to promote joint damage, also promote pain. We propose that activity-associated pain may occur through direct mechanical stimulation of peripheral nerve termini or through secondary production of pro-algesic molecules by other joint tissues (including cartilage, which is aneural). This hypothesis will be addressed through the following aims: Aim 1: Evaluate responses of peripheral sensory nerve termini within joint tissues to mechanical stimuli after destabilization of the medial meniscus (DMM) in the mouse; Aim 2: Determine which mechanical stimuli can induce pro-algesic molecule production by chondrocytes; Aim 3: Identify classes of ion channels expressed by chondrocytes and evaluate mechanical function.