Obesity promoting protein malonylation and chondrocyte metabolic dysfunction in osteoarthritis development

肥胖促进骨关节炎发展中的蛋白质丙二酰化和软骨细胞代谢功能障碍

• 批准号: 10424671
• 负责人: Shouan Zhu
• 金额: $ 45.3万
• 依托单位: OHIO UNIVERSITY ATHENS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10424671
• 关键词: ADAMTS; Acetylation; Adult; Affect; Age; Age-Years; Aging; Area; Binding; Biological Assay; Biomedical Research; Blood; Bone Spur; Carbon; Cartilage; Cells; Chondrocytes; Collagen Type II; Contralateral; Data; Degenerative polyarthritis; Development; Disease; Elderly; Enzyme-Linked Immunosorbent Assay; Enzymes; Epitopes; Future; Genes; Genetic Models; Genus Hippocampus; Goals; Hand; Head; High Fat Diet; Human; Impairment; In Vitro; Incidence; Individual; Inflammation; Inflammatory; Interleukin-1 beta; Joints; Knee Osteoarthritis; Knowledge; Lead; Link; Literature; Longevity; Mass Fragmentography; Matrix Metalloproteinases; Measures; Mediating; Metabolic; Metabolic Control; Metabolic dysfunction; Metabolism; Methods; Mission; Mus; Obese Mice; Obesity; Obesity Epidemic; Ohio; Overnutrition; Oxygen Consumption; Pathology; Pharmaceutical Preparations; Phenotype; Play; Post-Translational Protein Processing; Prevalence; Process; Proteins; Public Health; Regulator Genes; Regulatory Pathway; Reporting; Research; Reverse Transcriptase Polymerase Chain Reaction; Risk; Risk Factors; Role; Serum; Signal Pathway; Sirtuins; Stress; Students; Synovitis; Testing; Therapeutic; Tissues; Training; United States National Institutes of Health; Universities; Work; adverse outcome; aggrecan; base; cartilage degradation; cost; diet-induced obesity; disability; effective intervention; gene synthesis; graduate student; in vivo; joint destruction; joint loading; mechanical load; mouse genetics; mouse model; new therapeutic target; novel; obesity biomarkers; prevent; programs; public health relevance; student mentoring; theories; tissue procollagenase; undergraduate student

Project Summary/Abstract Most older adults (~70 years of age) have some signs of osteoarthritis (OA) in their joints. Development of OA can also be accelerated by ~20 years in individuals who are obese. This phenomenon does not stem solely from greater mechanical loading, obesity also increases OA risk in non-weight-bearing hand joints. Obesity can produce adverse outcomes in part because it alters metabolism at both a whole-body level and a cellular level. However, it is unknown how joint cells change metabolism during aging and obesity. Identifying metabolic changes in joint cells during aging and obesity could inform effective interventions and therapeutic strategies that reduce the incidence and impact of OA, especially in the context of an increasing prevalence of obesity and extended lifespans. This project will investigate a new theory of cell metabolic damage called "carbon stress", which describes how over-nutrition causes metabolic byproducts to accumulate in cells, bind to metabolic proteins, and decrease protein activity. We hypothesize that obesity-associated ‘carbon stress’ also occurs in cartilage (chondrocytes) and plays an important role in OA development. Our previous work shows that one type of carbon stress associated with protein post-translational malonylation (MaK) is highly elevated in cartilage during obesity. We also showed that Sirt5, an enzyme that can remove MaK, declines during aging, suggesting that cellular defenses against carbon stress are compromised during aging. Yet how do MaK and its regulatory pathways contribute to cellular metabolism in chondrocytes? Guided by our preliminary data and the literature, we will investigate this question via two specific aims: Aim 1. To test the hypothesis that obesity promotes MaK to accelerate OA development; Aim 2. To determine the mechanisms by which Sirt5-MaK regulates cartilage degeneration under obesity associated pro-inflammatory condition. Well-established mouse models of diet- induced obesity and OA will be used in combination with genetically modified mouse models that allow conditional deletion of MaK regulatory genes in cartilage. Mouse OA phenotyping will be used to examine the consequences of enhancing or inhibiting MaK on OA pathology. In vivo and in vitro metabolic profiling methods will be leveraged to determine the effects of manipulating MaK on chondrocyte cellular metabolism. Successful completion of this research is expected to provide more comprehensive understanding of how obesity and aging damage metabolism in joint cells and promote OA development, offering the potential to provide new therapeutic targets for OA treatment. The proposed project will also serve as a perfect vehicle for the PI to continue the on- going endeavor of mentoring students and engaging students in biomedical research.

项目总结/摘要 大多数老年人（约70岁）的关节都有骨关节炎（OA）的迹象。OA的发展 在肥胖的个体中也可以加速约20年。这一现象不仅源于 更大的机械负荷，肥胖也增加了非承重手关节的OA风险。肥胖会 产生不良后果的部分原因是它改变了全身水平和细胞水平的新陈代谢。 然而，尚不清楚关节细胞如何在衰老和肥胖期间改变代谢。识别代谢 衰老和肥胖期间关节细胞的变化可以为有效的干预和治疗策略提供信息 降低OA的发病率和影响，特别是在肥胖症患病率不断增加的情况下， 延长寿命该项目将研究一种称为“碳应激”的细胞代谢损伤新理论， 它描述了营养过剩如何导致代谢副产物在细胞中积累， 蛋白质，降低蛋白质活性。我们假设与肥胖相关的“碳压力”也发生在 软骨（软骨细胞），并在OA的发展中发挥重要作用。我们以前的工作表明， 与蛋白质翻译后丙二酰化（MaK）相关的碳应激在软骨中高度升高， 在肥胖期间。我们还发现，Sirt 5，一种可以去除MaK的酶，在衰老过程中下降，这表明 细胞对碳压力的防御在衰老过程中受到损害。然而，MaK及其监管机构如何 软骨细胞的代谢途径根据我们的初步数据和文献， 我们将通过两个具体目标来研究这个问题：目标1。为了验证肥胖促进MaK的假设， 加速OA发展;目标2.确定Sirt 5-MaK调节软骨的机制 在肥胖相关的促炎性病症下的变性。完善的饮食小鼠模型- 诱导肥胖和OA将与转基因小鼠模型联合使用， 软骨中MaK调节基因的条件性缺失。小鼠OA表型将用于检查 增强或抑制MaK对OA病理的影响。体内和体外代谢分析方法 将被用来确定操纵MaK对软骨细胞代谢的影响。成功 这项研究的完成有望提供更全面的了解肥胖和衰老是如何 破坏关节细胞的代谢，促进OA的发展，提供了提供新的治疗方法的潜力。 OA治疗的目标。建议的项目也将作为一个完美的工具，为PI继续- 指导学生并使学生参与生物医学研究的持续奋进。