Biomechanical Pathways Associated with Osteoarthritis Pain

与骨关节炎疼痛相关的生物力学途径

基本信息

批准号：
9307698
负责人：
Rachel Elizabeth Miller
金额：
$ 11.52万
依托单位：
RUSH UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9307698
关键词：
Academic Medical Centers Address Affect Afferent Neurons Area Arthritis Automobile Driving Award Basic Science Biochemistry Biology Biomechanics Biophysics Calcium Calcium Signaling Cartilage Cell physiology Cells Cellular biology Chemotactic Factors Chicago Chondrocytes Chronic Clinical Research Collaborations Collagen Collagen Type II Communities Complement Custom Data Degenerative polyarthritis Development Disease Doctor of Philosophy Electrophysiology (science)Environment Enzyme-Linked Immunosorbent Assay Equipment Extracellular Matrix Faculty Funding Generations Goals Human Image Immunohistochemistry In Situ Institutes Internal Medicine Ion Channel Joints K-Series Research Career Programs Knee Knee Osteoarthritis Knee joint Laboratories Lead Manuscripts Mechanical Stimulation Mechanics Medial meniscus structure Mediating Medical Medicine Membrane Mentored Research Scientist Development Award Mentorship Methods Modeling Molecular Mus Musculoskeletal Nerve Neurobiology Neurons Neurosciences Operative Surgical Procedures Orthopedics Pain Pathologic Pathway interactions Peripheral Peripheral Nerve Stimulation Peripheral Nerves Physiology Play Positioning Attribute Production Proteins Publications Reporter Research Research Personnel Research Proposals Research Training Resource Development Rheumatology Role Science Signal Pathway Signal Transduction Sodium Channel Source Spinal Ganglia Stimulus Stream Stress Stretching Study models Subcellular Anatomy Symptoms System Techniques Therapeutic Time Tissues Training Transgenic Organisms Translating Translational Research United States Universities Walking Weight-Bearing state Western Blotting Work Writing afferent nerve bridge program calcium indicator career development chronic pain experience forging functional disability improved in vivo insight joint injury lectures mechanical force mechanical load meetings member monocyte novel post-doctoral training prevent professor programs promoter protein expression receptor release of sequestered calcium ion into cytoplasm research study response responsible research conduct sham surgery voltage

项目摘要

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.

项目摘要候选人：Rachel E. Miller博士是Rush的医学助理教授（风湿病科）伊利诺伊州芝加哥大学医学中心。米勒博士正在寻求指导的研究科学家发展为了获得对神经生物学和生理实验室技术的额外培训的奖励她制定一个独立的研究计划，重点是更好地理解 OA疼痛。具体而言，米勒博士将接受电生理学和钙信号技术的培训，作为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其他专业知识所需的其他专业知识来补充她的毕业生和博士后培训锻造独立的研究计划桥接：肌肉骨骼生物学，生物力学，神经科学和生理。预计这项研究将提供有关负责的信号通路的新见解与异常机械负荷相关的疼痛，最终可以翻译成改进的疼痛 OA的治疗剂。该奖项将使她能够将75％的FTE投入到提议的培训和科学上。在除科学培训外，她还将受益于研讨会和科学的演讲会议，负责任进行研究的培训以及手稿写作的培训和授予技巧。环境：米勒博士最近在拉什大学接受了该系的助理教授职位内科，风湿病科。拉什关节炎和骨科研究所，包括骨科，解剖与细胞生物学，风湿病学和生物化学的部门提供了学术转化研究社区结合了出色的基础研究和临床研究骨关节炎。此外，与西北医学校园的近距离接近允许密切合作具有神经科学和生理学专家。最后，分子系的教职员工 Rush的生物物理学和生理学在各个领域都有积极的研究计划，包括功能细胞膜和离子渠道的经验，其经验将使米勒博士提出的研究受益。博士米勒得到了风湿病学的全部支持，该部门保证米勒博士将整个奖项期间，超过75％的时间对K01相关的研究和培训受到保护，并追求本申请的目标，她将拥有最低的行政，委员会和演讲义务。她将可以访问所有教师专业知识，指导，实验室空间和设备，以及所需的职业发展资源，以帮助她实现成为独立的目标研究员。研究：该提案重点是提高对体重活动导致疼痛的理解骨关节炎。膝盖的骨关节炎（OA）是一种疼痛疾病，其特征是进行性损害和所有关节组织的重塑。异常机械力在推动发展方面起着重要作用膝盖OA。在承重活动中，包括步行和攀爬楼梯，损坏的区域为遭受增加的局灶性应力，从而导致更多损坏。相同的体重活动是与OA疼痛有关。长期刺激感觉神经（例如在OA中）可能导致敏化和慢性疼痛。因此，与机械输入相关的早期OA疼痛治疗可能对防止慢性疼痛。我们的假设是膝关节内的异常机械力，已知促进关节损害，也会促进疼痛。我们建议通过直接发生与活动相关的疼痛机械刺激周围神经末端或通过二次产生促脂分子的机械刺激其他关节组织（包括软骨，是动脉化的）。该假设将通过以下目的：目标1：评估关节组织内周围感觉神经末端对内侧半月板（DMM）在小鼠中稳定后的机械刺激；目标2：确定哪个机械刺激可以诱导软骨细胞产生促吻合分子。目标3：确定离子类由软骨细胞表达并评估机械功能的通道。