Biomechanical Pathways Associated with Osteoarthritis Pain

项目摘要 候选人：雷切尔E。米勒博士是拉什大学医学（流变学系）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个指导研究科学家的发展 为了获得必要的神经生物学和生理学实验室技术的额外培训， 她开发了一个独立的研究计划，重点是更好地了解机械生理学， OA疼痛。具体来说，米勒博士将接受电生理学和钙信号技术的培训， 以及应用定制机械加载的培训。因此，这个职业发展奖将 补充她的研究生和博士后培训，为她提供必要的额外专业知识， 打造一个独立的研究计划桥接：肌肉骨骼生物学，生物力学，神经科学， physiology.这项研究预计将提供新的见解信号通路负责 与异常机械负荷相关的疼痛，这最终可以转化为改善 OA的治疗方法。该奖项将使她能够将75%的FTE用于拟议的培训和科学。在 除了科学培训，她将受益于出席和介绍研讨会和科学 会议、负责任地开展研究的培训、撰写论文的培训， granuate. 环境：米勒博士最近接受了拉什大学环境系助理教授的职位。 内科，风湿病学分部。拉什关节炎和骨科研究所，包括 骨科，解剖学和细胞生物学，流变学和生物化学系，提供了一个学术 转化研究社区，结合了优秀的基础和临床研究的研究， 骨关节炎此外，靠近西北医学院，可以进行密切合作。 神经科学和生理学的专家最后，分子系的教职员工 拉什的生物物理学和生理学在各个领域都有积极的研究计划，包括功能 他的经验将有助于米勒博士的研究。博士 米勒有流变学分部的全力支持，该分部保证米勒博士将 在整个合同期限内，超过75%的时间用于K 01相关的研究和培训， 追求这个应用程序的目标，她将有最低限度的行政，委员会，和讲课 义务她将有机会获得所有的教师专业知识，导师，实验室空间和设备， 和必要的职业发展资源，以帮助她实现成为一个独立的目标， 研究员 研究：这项提案的重点是提高对为什么负重活动会导致疼痛的理解， 骨关节炎膝关节骨关节炎（OA）是一种疼痛性疾病，其特征在于进行性损伤， 所有关节组织的重塑。异常机械力在推动 膝关节OA。在负重活动中，包括行走和爬楼梯，受损区域 受到更大的集中应力，导致更多的损伤。同样的负重活动 与OA疼痛相关。感觉神经的慢性刺激，如OA，可能导致致敏 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， 促进关节损伤也促进疼痛。我们认为，活动相关性疼痛可能通过直接 机械刺激外周神经末梢或通过次级产生痛觉原分子， 其他关节组织（包括软骨，这是神经）。这一假设将通过 以下目的：目的1：评价关节组织内外周感觉神经末梢对 在小鼠内侧半月板（DMM）不稳定后的机械刺激;目的2：确定 机械刺激可诱导软骨细胞产生促痛分子;目的3：确定离子种类 通道由软骨细胞表达并评估机械功能。

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.