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.

项目概要候选人：Rachel E. Miller 博士，Rush 医学助理教授（风湿病科）大学医学中心，芝加哥，伊利诺伊州。米勒博士正在寻求指导研究科学家发展奖励以获得神经生物学和生理学实验室技术所需的额外培训她开发了一个独立的研究项目，重点是更好地理解机械生理学骨关节炎疼痛。具体来说，米勒博士将接受电生理学和钙信号技术方面的培训，因为以及应用定制机械负载的培训。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一个独立的研究项目桥接：肌肉骨骼生物学、生物力学、神经科学和生理。这项研究有望为负责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以转化为改善 OA 的治疗。该奖项将使她能够将 75% 的全职工作时间投入到拟议的培训和科学工作中。在除了科学培训外，她还将受益于参加研讨会和科学研讨会并进行演讲。会议、负责任的研究行为培训以及稿件写作和培训赠款。环境：米勒博士最近接受了拉什大学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、解剖学和细胞生物学、风湿病学和生物化学系，提供学术转化研究社区，结合了优秀的基础研究和临床研究骨关节炎。此外，靠近西北医学校区，可以进行密切合作与神经科学和生理学专家一起。最后，分子系的老师们拉什的生物物理学和生理学在各个领域都有活跃的研究项目，包括功能细胞膜和离子通道的研究人员，其经验将有利于米勒博士提出的研究。博士。米勒得到了风湿病科的全力支持，该科保证米勒博士将有在整个奖项期间，超过 75% 的时间被保护用于与 K01 相关的研究和培训，并且为了实现本申请的目标，她将拥有最少的行政、委员会和讲座义务。她将获得所有教师的专业知识、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：该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) 是一种痛苦的疾病，其特征是进行性损伤和所有关节组织的重塑。异常机械力对机械的发展起着重要的驱动作用膝骨关节炎。在负重活动（包括步行和爬楼梯）中，受损区域受到更大的集中应力，导致更大的损坏。相同的负重活动与 OA 疼痛有关。感觉神经的慢性刺激（例如骨关节炎）可能会导致过敏和慢性疼痛。因此，治疗与机械输入相关的早期 OA 疼痛对于预防慢性疼痛。我们的假设是膝关节内异常的机械力，已知促进关节损伤，也会加剧疼痛。我们建议，与活动相关的疼痛可能通过直接发生周围神经末梢的机械刺激或通过促痛分子的二次产生其他关节组织（包括软骨，无神经）。这一假设将通过以下目标：目标 1：评估关节组织内周围感觉神经末梢的反应小鼠内侧半月板 (DMM) 不稳定后的机械刺激；目标 2：确定哪个机械刺激可诱导软骨细胞产生促痛分子；目标 3：识别离子类别软骨细胞表达的通道并评估机械功能。