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; 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 这种重新进入的补充剂将支持Priyanka Brahmachary博士的博士后研究。所有细胞都是 受压缩等机械力的作用和响应，该项目的目的是（1） 研究体内软骨细胞的葡萄糖代谢，（2）描述高脂饮食对 小鼠的滑膜联合机械转导。但是，连接力学的分子机制 生物学反应尚未完全理解。我们模型系统的细胞，软骨细胞 关节软骨，体内受压，这些​​细胞可以将压缩转换为 生物信号。有证据表明，软骨细胞中的葡萄糖利用受压缩调节 生理压缩刺激糖酵解，当前接受的软骨细胞 用于制作ATP。这种现象与软骨细胞保持软骨的能力有关。 该项目检验了一个假说，即正常和骨关节炎的生理压缩 软骨细胞导致葡萄糖代谢中代谢物的特定模式支持蛋白 生产以维持细胞微环境。前提是通过量化葡萄糖 软骨细胞中的代谢这些研究将推动使用机械载荷生产的策略 软骨维修的构件。 AIM 1-使用经受自愿运行的小鼠的实验 将评估体内机械转导。因变量包括性别和跑步持续时间。 读数将包括靶向代谢物和免疫组织学标记，以检查调节 葡萄糖代谢。测定将采用高度特定的酶抑制剂，以逐步进行 临界代谢途径的分析。目标2-肥胖是相关的重要风险因素之一 与OA有关，与OA病理学之前的慢性和全身性炎症有关。研究 表明血液代谢物水平的变化也随着组织和身体成分的变化而导致 在OA的发病机理中起作用。使用喂养高脂肪饮食并暴露于自愿的小鼠的实验 运动将有助于了解软骨细胞中的葡萄糖代谢以及 机械传导到OA发病机理。使用涉及特定的多学科方法 免疫组织化学标记和靶向代谢产物，我们将分析效果和潜在 OA的肥胖相关进展及其对软骨细胞的作用的分子机制。 了解这些机制可能对制定翻译策略有用 通过激活现有的机械敏感途径来软骨。了解软骨细胞如何反应 压缩将通过为软骨提供新的治疗靶点来推动骨关节炎的翻译 修复并实现实质性临床进展。