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.

项目摘要/摘要 大多数老年人(约70岁)的关节有一些骨关节炎(OA)的迹象。办公自动化的发展 对于肥胖的人来说，也可以加速大约20年。这种现象不仅仅源于 更大的机械负荷，肥胖也会增加非负重手关节的骨性关节炎风险。肥胖可以 产生不良后果的部分原因是它改变了全身和细胞水平的新陈代谢。 然而，关节细胞在衰老和肥胖过程中如何改变新陈代谢尚不清楚。确定代谢 衰老和肥胖过程中关节细胞的变化可以为有效的干预和治疗策略提供依据 减少骨质疏松症的发生率和影响，特别是在肥胖率和 延长寿命。该项目将研究一种新的细胞代谢损伤理论，称为“碳应激”， 它描述了过度营养如何导致代谢副产物在细胞内积累，与代谢结合 蛋白质，并降低蛋白质活性。我们假设肥胖相关的“碳压力”也发生在 软骨(软骨细胞)在骨性关节炎的发生发展中起着重要作用。我们之前的工作表明，有一种类型 翻译后丙二酸化蛋白(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，SIRT5，一种可以清除MAK的酶，在衰老过程中会下降，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及其监管机构是如何 软骨细胞的代谢途径对细胞代谢有贡献吗？根据我们的初步数据和文献， 我们将通过两个具体的目标来研究这个问题：目标1.检验肥胖促进Mak的假设 促进骨性关节炎的发生；目的2.确定SIRT5-Mak调节软骨的机制 肥胖相关的促炎状态下的变性。成熟的小鼠饮食模型- 诱导性肥胖和骨性关节炎将与转基因小鼠模型结合使用， 软骨中Mak调控基因的条件性缺失。将使用小鼠的OA表型来检查 增强或抑制MAK对骨关节炎病理的影响。体内和体外代谢谱方法 将被用来确定操纵MAK对软骨细胞细胞代谢的影响。成功 这项研究的完成有望更全面地了解肥胖和衰老是如何 破坏关节细胞的代谢，促进骨性关节炎的发展，为提供新的治疗方法提供了潜力 骨性关节炎治疗的靶点。拟议的项目也将成为私募股权投资公司继续开展- 努力辅导学生，让学生参与生物医学研究。