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.

项目概要/摘要 大多数老年人（约 70 岁）的关节都有一些骨关节炎 (OA) 的迹象。办公自动化的发展 肥胖者的年龄也可加快约 20 年。这一现象不仅仅源于 更大的机械负荷，肥胖也会增加非负重手关节的骨关节炎风险。肥胖可以 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，尚不清楚关节细胞在衰老和肥胖期间如何改变新陈代谢。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措施和治疗策略提供信息 减少 OA 的发生率和影响，特别是在肥胖和肥胖患病率不断增加的背景下 延长使用寿命。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，并与代谢结合 蛋白质，并降低蛋白质活性。我们假设与肥胖相关的“碳压力”也发生在 软骨（软骨细胞）在 OA 发展中起着重要作用。我们之前的工作表明，一种类型 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 肥胖期间。我们还发现 Sirt5（一种可以去除 MaK 的酶）在衰老过程中会下降，这表明 细胞对碳应激的防御在衰老过程中受到损害。然而 MaK 及其监管机构如何 途径有助于软骨细胞的细胞代谢？在我们的初步数据和文献的指导下， 我们将通过两个具体目标来研究这个问题： 目标 1. 检验肥胖促进 MaK 的假设 加快OA发展；目标 2. 确定 Sirt5-MaK 调节软骨的机制 肥胖相关促炎症条件下的退化。完善的饮食小鼠模型 诱导性肥胖和 OA 将与转基因小鼠模型结合使用，从而允许 有条件地删除软骨中的 MaK 调节基因。小鼠 OA 表型分析将用于检查 增强或抑制 MaK 对 OA 病理学的影响。体内和体外代谢分析方法 将用于确定操纵 MaK 对软骨细胞代谢的影响。成功的 这项研究的完成预计将更全面地了解肥胖与衰老之间的关系 损害关节细胞的代谢并促进 OA 的发展，有望提供新的治疗方法 OA 治疗的目标。拟议的项目也将作为 PI 继续进行研究的完美工具。 持续努力指导学生并让学生参与生物医学研究。