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

基本信息

批准号：
10612757
负责人：
Erica Valentine Ely
金额：
$ 4.77万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
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/10612757
关键词：
Address Affect American Animal Model Animals Antibodies Atomic Force Microscopy Attenuated Biological Biomechanics Body fat Calcium Calcium Signaling Calcium ion Cartilage Cations Cell Death Inhibition Cells Cessation of life Chondrocytes Circulation 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 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 Traumatic Arthropathy Up-Regulation Western Blotting adipokines aggrecan behavior test bone cell type chondroprotection 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

项目摘要

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.

项目概要骨关节炎 (OA) 是一种使滑膜关节衰弱的疾病，是导致疼痛和残疾的主要原因全球有超过 3000 万美国人受到 OA 的影响，但目前还没有治疗肥胖的药物。然而，很难将低水平全身炎症与 OA 的危险因素区分开来。随着体重增加而改变的关节负荷的影响，而软骨需要负荷来维持组织。体内平衡，之前的研究表明，由于体重增加导致的异常负荷可以解释为什么与健康体重的人相比，肥胖者的软骨损伤率更高然而，许多最近的研究表明，体重增加本身并不能解释 OA。人类和动物模型中的损伤，脂肪因子（来自体内脂肪的炎症介质）发挥着此外，Guilak 实验室之前的研究强调了协同作用。机械敏感离子通道 Piezo1 和 Piezo2 在软骨健康和维护中的重要性：肥胖和 OA 相关炎症介质白细胞介素 1 α (IL-1α) 可调节 Piezo 并使其敏感因此，该提案研究了细胞因子/脂肪因子信号传导是否是其机制。压电通道对机械力变得高度敏感，最终导致软骨细胞死亡增加。该提案的目标是直接研究肥胖相关炎症和肥胖相关炎症之间的相互作用。软骨细胞的机械敏感性这项关于机械感觉改变在发病机制中的作用的研究。 OA 与肥胖的关系将导致针对这些途径开发治疗新药的最终目标具体目标 1 侧重于确定肥胖相关炎症是否会改变 Piezo。软骨中的表达，如果这种增加的表达转化为增加软骨细胞对这项研究重点关注与肥胖相关的关键脂肪因子失调：IL-1α、瘦素、肿瘤坏死。 α因子 (TNF-α) 和白细胞介素 6 (IL-6) 具体目标 2 使用先前在实验室研究软骨细胞特异性 Piezo1 和/或 Piezo2 离子通道的丧失是否可以预防软骨损伤具体而言，小鼠将被喂食高脂肪饮食（60％的脂肪）并在肥胖和关节损伤的体内模型中进行损伤。接受了内侧半月板不稳定 (DMM) 手术，已知会引起创伤后 OA。两个目标共同战略性地开发原子力显微镜 (AFM) 和钙 (Ca2+) 成像技术对软骨完整性进行体内评估，以补充转基因小鼠在模型中的使用 HFD 与 DMM 损伤叠加本研究的结果将有助于确定其机制。肥胖影响软骨健康，最终导致骨关节炎疾病缓解药物的开发，这可能可以更广泛地应用于受压电离子通道机械感觉改变影响的其他组织。