The Multiscale Role of Piezo Channels in Obesity-Associated Cartilage Damage

压电通道在肥胖相关软骨损伤中的多尺度作用

• 批准号: 10387891
• 负责人: Erica Valentine Ely
• 金额: $ 4.68万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10387891
• 关键词: Address; Affect; American; Animal Model; Animals; Antibodies; Atomic Force Microscopy; Attenuated; Biological; Biomechanics; Blood Circulation; Body fat; Calcium; Cartilage; Cations; Cell Death; Cells; Cessation of life; Chondrocytes; Complement; Confocal Microscopy; Degenerative polyarthritis; Development; Disease; Esthesia; Exposure to; Fatty acid glycerol esters; Goals; Harvest; Health; High Fat Diet; High Prevalence; Hindlimb; Histology; Homeostasis; Hypersensitivity; Imaging Techniques; Immunohistochemistry; In Vitro; Individual; Inflammation; Inflammation Mediators; Inflammatory; Interleukin-1 alpha; Interleukin-6; Ion Channel; Ions; Joints; Knee joint; Knock-out; Length; Leptin; Link; Maintenance; Measurement; Measures; Mechanical Stress; Mechanics; Medial meniscus structure; Messenger RNA; Modeling; Monitor; Mus; Obesity; Operative Surgical Procedures; Pain; Pathogenesis; Pathologic; Pathway interactions; Pharmaceutical Preparations; Physiological; Piezo 1 ion channel; Piezo 2 ion channel; Piezo ion channels; Play; Proteins; Risk Factors; Role; Scanning Probe Microscopes; Serum; Signal Transduction; Synovial Fluid; Synovial joint; TNF gene; Testing; Tissues; Training; Transgenic Mice; Translating; Trauma; Up-Regulation; Western Blotting; adipokines; aggrecan; behavior test; bone; cell type; cytokine; disability; experience; graduate student; healthy weight; human model; in vivo; in vivo Model; inflammatory milieu; inhibitor; insight; joint injury; joint loading; knock-down; mechanical force; mechanical load; mechanotransduction; medical specialties; meniscus injury; microCT; mouse genetics; mouse model; novel therapeutic intervention; protein expression; response; sensor; systemic inflammatory response; therapeutic target

PROJECT SUMMARY Osteoarthritis (OA) is a debilitating disease of the synovial joints and is the leading cause of pain and disability worldwide. OA affects over 30 million Americans, but there are no disease modifying drugs. Obesity is a major risk factor for OA; however, it has been difficult to disentangle the role of low-level systemic inflammation from the effects of altered joint loading with increased body mass. While cartilage requires loading to maintain tissue homeostasis, previous studies have suggested that abnormal loading due to increased body mass may explain why individuals with obesity experience cartilage damage at elevated rates when compared to healthy weight individuals. However, many recent studies demonstrate that increased body mass alone does not explain OA damage in human and animal models, and that adipokines, inflammatory mediators from body fat, play an important role in OA pathogenesis. Additionally, previous studies from the Guilak lab highlight the synergistic importance of the mechanosensitive ion channels Piezo1 and Piezo2 in cartilage health and maintenance: obesity and an OA-relevant inflammatory mediator, interleukin 1 alpha (IL-1α), modulates and sensitizes Piezo channel function. As such, this proposal investigates if cytokine/adipokine signaling is the mechanism by which Piezo channels become hypersensitized to mechanical force, ultimately leading to increased chondrocyte death. The goal of this proposal is to directly investigate the interaction between obesity-associated inflammation and the mechanosensitivity of chondrocytes. This study on the role of altered mechanosensation in the pathogenesis of OA with obesity will lead to the ultimate goal of targeting these pathways to develop novel therapeutic approaches. Specific Aim 1 focuses on determining if obesity-associated inflammatory conditions alter Piezo expression in cartilage and if this increased expression translates to increased chondrocyte sensitivity to mechanical loads. This study hones in on key dysregulated adipokines with obesity: IL-1α, Leptin, tumor necrosis factor alpha (TNF-α), and interleukin 6 (IL-6). Specific Aim 2 uses transgenic mice previously developed in the lab to investigate if the loss of chondrocyte-specific Piezo1 and/or Piezo2 ion channels protects against cartilage damage in an in vivo model of obesity and joint injury. Specifically, mice will be fed a high-fat diet (60% fat) and subjected to a destabilization of the medial meniscus (DMM) surgery, known to evoke post-traumatic OA. Together, both aims strategically develop atomic force microscopy (AFM) and calcium (Ca2+) imaging techniques with in vivo assessments of cartilage integrity to complement the use of genetically-modified mice in a model of HFD superimposed with DMM injury. The results from this study will help identify the mechanisms by which obesity affects cartilage health, ultimately leading to the development of OA disease modifying drugs, that may be more broadly applied to other tissues affected by altered mechanosensation of Piezo ion channels.

项目总结