Research Supplements to Promote Re-Entry: Role of Glucose metabolism in Chondrocyte Mechanotransduction

促进重返的研究补充剂：葡萄糖代谢在软骨细胞机械转导中的作用

• 批准号: 10086619
• 负责人: Ronald Kent June
• 金额: $ 12.05万
• 依托单位: MONTANA STATE UNIVERSITY - BOZEMAN
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10086619
• 关键词: Accounting; Address; Affect; Age; Aging; Arthritis; Biochemical Reaction; Biological; Biological Assay; Biological Models; Biology; Blood; Body Composition; Body Weight decreased; Body fat; Cartilage; Cartilage Matrix; Cells; Chondrocytes; Chronic; Citric Acid Cycle; Clinical; Complex; Data; Degenerative polyarthritis; Development; Elderly; Energy-Generating Resources; Environment; Enzyme Inhibitor Drugs; Exercise; Exposure to; FDA approved; Fatty acid glycerol esters; Female; Genetic; Glucose; Glutamine; Glycolysis; Health Expenditures; High Fat Diet; Histopathology; Immunohistochemistry; Individual; Inflammation; Isotope Labeling; Isotopes; Joints; Knee Injuries; Link; Liquid substance; Mass Spectrum Analysis; Mechanics; Metabolic; Metabolic Pathway; Metabolism; Modeling; Molecular; Movement; Mus; Musculoskeletal System; Non-Essential Amino Acid; Obesity; Pain; Pathogenesis; Pathology; Pathway interactions; Patients; Pattern; Pentosephosphate Pathway; Pharmaceutical Preparations; Physiological; Plasma; Play; Process; Production; Proteins; Replacement Arthroplasty; Research; Respiration; Risk Factors; Role; Running; Sampling; Signal Transduction; Stains; Stimulus; Symptoms; Synovial Membrane; Synovial joint; Testing; Tissues; Translations; Walking; articular cartilage; blood glucose regulation; bone; bone cell; cartilage repair; cell type; disability; experimental study; glucose metabolism; healing; immunohistochemical markers; in vivo; inflammatory marker; insight; interdisciplinary approach; joint destruction; joint loading; male; mechanical force; mechanical load; mechanotransduction; metabolomics; new therapeutic target; productivity loss; repaired; response; sex; small molecule inhibitor; translational approach

Project Summary This re-entry supplement will support postdoctoral studies of Dr. Priyanka Brahmachary. All cells are subject to and respond to mechanical forces like compression, and the aims of this project are (1) to study glucose metabolism by chondrocytes in vivo and (2) to delineate the effects of a High Fat Diet on synovial joint mechanotransduction in mice. However, the molecular mechanisms linking the mechanics to biological responses are not fully understood. The cells of our model system, the chondrocytes of articular cartilage, undergo compression in vivo, and these cells can transduce compression into biological signals. There is evidence that glucose utilization in chondrocytes is regulated by compression and that physiologic compression stimulates glycolysis, the currently accepted pathway chondrocytes use to make ATP. This phenomenon has been linked to the ability of chondrocytes to maintain cartilage. This project tests the hypothesis that physiological compression of both normal and osteoarthritic chondrocytes results in a specific pattern of metabolites within glucose metabolism that support protein production to maintain the cellular microenvironment. The premise is that by quantifying glucose metabolism in chondrocytes these studies will advance strategies that use mechanical loading to produce the building blocks for cartilage repair. Aim 1 - Experiments using mice subjected to voluntary running will assess in vivo mechanotransduction. Dependent variables include sex and the duration of running. Readouts will include both targeted metabolites and immunohistological markers examining regulation of glucose metabolism. Assays will employ highly specific enzyme inhibitors that will allow a step-by-step analysis of critical metabolic pathways. Aim 2 - Obesity is one of the important risk factors associated with OA and is associated with chronic and systemic inflammation that precedes OA pathology. Studies show that changes in blood metabolite levels, as a result of change in tissue and body composition also play a role in the pathogenesis of OA. Experiments using mice fed a high fat diet and exposed to voluntary exercise will help understand glucose metabolism in chondrocytes as well as the relation of mechanotransduction to OA pathogenesis. Using a multidisciplinary approach involving specific immunohistochemical markers and targeted metabolites, we will analyze the effects and underlying molecular mechanisms of obesity related progression of OA and its effects on chondrocytes. Understanding these mechanisms may prove useful in developing translational strategies to heal cartilage by activating existing mechanosensitive pathways. Insight into how chondrocytes respond to compression will advance osteoarthritis translation by providing new therapeutic targets for cartilage repair and enabling substantial clinical progress.

项目摘要 这个再进入补充将支持博士的博士后研究。所有细胞 承受并响应机械力，如压缩，本项目的目的是（1） 研究体内软骨细胞的葡萄糖代谢;（2）描述高脂饮食对 滑膜关节机械转导。然而，连接机械的分子机制 对生物反应的影响还不完全清楚。我们的模型系统的细胞， 关节软骨，在体内经历压缩，并且这些细胞可以将压缩转化为 生物信号有证据表明，软骨细胞中的葡萄糖利用是受压缩调节的 生理性压迫刺激糖酵解，目前公认的途径软骨细胞 用来制造ATP。这种现象与软骨细胞维持软骨的能力有关。 该项目测试了正常骨关节炎和骨关节炎的生理压缩的假设 软骨细胞在葡萄糖代谢中产生特定的代谢物模式， 生产以维持细胞微环境。前提是通过定量葡萄糖 这些研究将推进使用机械负荷来产生 软骨修复的基石目的1 -使用自愿跑步的小鼠的实验 将评估体内机械传导。因变量包括性别和跑步的持续时间。 读数将包括靶向代谢物和免疫组织学标记物，检查细胞内的 葡萄糖代谢检测将采用高度特异性的酶抑制剂， 关键代谢途径的分析。目标2 -肥胖是与肥胖相关的重要危险因素之一 与OA相关，并与OA病理学之前的慢性和全身性炎症相关。研究 表明由于组织和身体成分变化，血液代谢物水平的变化也 在OA的发病机制中发挥作用。实验使用高脂肪饮食喂养的小鼠，并暴露于自愿的 运动将有助于了解软骨细胞中的葡萄糖代谢以及 机械传导对OA发病机制的影响。采用多学科方法， 免疫组织化学标记物和靶向代谢物，我们将分析的影响和基础 肥胖相关OA进展的分子机制及其对软骨细胞的影响。 了解这些机制可能有助于发展翻译策略，以愈合 通过激活现有的机械敏感途径来修复软骨。深入了解软骨细胞如何响应 压缩将通过为软骨提供新的治疗靶点来促进骨关节炎的转移 修复并使临床取得实质性进展。