The Role of Fat in Osteoarthritis

脂肪在骨关节炎中的作用

• 批准号: 10609017
• 负责人: Kelsey Helen-Marie Collins
• 金额: $ 0.67万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-24 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10609017
• 关键词: Address; Adipocytes; Adipose tissue; Affect; Animals; Anti-Inflammatory Agents; Area; Bioinformatics; Biological; Biomechanics; Biomedical Engineering; Body fat; CRISPR/Cas technology; Cardiovascular Diseases; Cartilage; Cell Differentiation process; Cell Line; Cells; Chondrocytes; Chronic Disease; Clinical; Complement Factor D; Complex; Consumption; Degenerative polyarthritis; Development; Diabetes Mellitus; Disease; Engineering; Fatty acid glycerol esters; Future; Gene Deletion; Generations; Genetic Transcription; Genome engineering; Goals; Grant; Health; High Fat Diet; Homeostasis; Hormones; Implant; In Vitro; Individual; Inflammation; Inflammation Mediators; Inflammatory; Injury; Insulin Resistance; Interleukin-10; Joints; Knee Injuries; Knee joint; Knock-out; Lead; Leptin; Link; Lipodystrophy; Malignant Neoplasms; Mediator; Mentors; Metabolic; Metabolic syndrome; Monoclonal Antibodies; Mus; Muscle Weakness; Obesity; Oils; Operative Surgical Procedures; Pain; Pathogenesis; Pathologic; Pharmaceutical Preparations; Play; Positioning Attribute; Predisposition; Proteomics; Regenerative Medicine; Reporting; Research; Research Personnel; Role; Satiation; Signal Transduction; Source; Stains; Testing; Therapeutic; Time; Training; Transgenic Mice; Transplantation; Traumatic Arthropathy; adipokines; aggrecan; career; cell type; combat; design; disability; flexibility; genome editing; implantation; improved; in vivo; induced pluripotent stem cell; interest; joint destruction; mouse model; novel; novel strategies; patient population; programs; promoter; protective effect; regenerative therapy; resistin; response; subchondral bone; synthetic biology; systemic inflammatory response; tool; transcriptome sequencing; translational therapeutics

PROJECT SUMMARY Osteoarthritis (OA) is the leading cause of pain and disability worldwide, and there are currently no disease modifying treatments available. While obesity-induced OA involves both metabolic and biomechanical factors, a key link is excess fat, or adipose tissue – a source of inflammatory mediators implicated in the pathogenesis of OA. The mechanistic influence of adiposity, biomechanical alterations, and metabolic syndrome have been difficult to determine and disentangle. To separate these factors, we used a mouse model of lipodystrophy (LD), in which the animals completely lack fat but maintain normal body mass. The LD mouse demonstrates many clinical signs observed in individuals with obesity-induced OA (sclerotic subchondral bone, systemic inflammation, insulin resistance, metabolic disturbance, and muscle weakness). Unexpectedly, we observed that LD knee joints are protected from OA. When fat was transplanted into LD mice protection from OA was reversed, implicating that adipose tissue, and factors secreted by adipose tissue called adipokines – but not body weight – are critical mediators of joint degeneration. These results suggest that adipose tissue and the mediators (adipokines) secreted by adipose tissue adversely affect cartilage health. In the mentored K99 portion of this grant, we will generate bioengineered designer adipose implants using murine induced pluripotent stem cells (iPSCs) to provide a platform to deconstruct adipokine signaling and investigate the mechanisms linking adipose tissue and joint health. This approach, which was not possible previously without creating complex and expensive transgenic mice, addresses a gap fundamental in our understanding of obesity and OA. In the independent R00 portion of this grant, we will leverage recent advances in regenerative medicine to develop and test a self-regulating cell-based implant that can provide biologic drugs to combat OA, laying the platform for Dr. Collins’ independent research career, and the groundwork for a first R01. The value of this platform is the flexibility to interchangeably deliver a wide range of potential therapeutics. Using this novel and flexible platform, we will hijack adipokine signaling to deliver anti-inflammatory mediators in a tunable and well- controlled manner as a novel regenerative therapy for OA. Since this iPSC platform could readily accommodate edits and alterations of targets of interest in a variety of cell types, the potential for this therapy is far-reaching, as many chronic diseases (cancer, cardiovascular disease, diabetes, etc.) have links to pathologic inflammatory signaling.

项目摘要 骨关节炎（OA）是全球疼痛和残疾的主要原因，目前没有疾病 可用的治疗方法。肥胖引起的OA涉及代谢和生物力学因素，但 关键联系是多余的脂肪或脂肪组织 - 在 OA。肥胖，生物力学改变和代谢综合征的机械影响一直是 难以确定和解开。为了分离这些因素，我们使用了脂肪营养不良（LD）的小鼠模型， 动物完全缺乏脂肪，但保持正常体重。 LD鼠标展示了许多 在肥胖诱导的OA（硬化下骨，全身性）的个体中观察到的临床体征 炎症，胰岛素抵抗，代谢灾难和肌肉无力）。出乎意料的是，我们观察到 LD膝关节免受OA的保护。当将脂肪移植到LD小鼠免受OA保护中时，逆转 隐含脂肪组织，以及被称为脂肪因子的脂肪组织分泌的因素，但不是体重 - 是关节变性的关键介体。这些结果表明脂肪组织和介体 （脂肪因子）由脂肪组织分泌，对软骨健康产生不利影响。 在该赠款的修订K99部分中，我们将使用Murine生成生物工程设计的设计师脂肪 诱导多能干细胞（IPSC）提供一个平台来解构脂肪因子信号并研究 连接脂肪组织和关节健康的机制。这种方法，以前是不可能的 创建复杂且昂贵的转基因小鼠，解决了我们对肥胖症的理解的差距 和OA。在这笔赠款的独立r00部分中，我们将利用重生医学的最新进展 开发和测试可以提供生物学药物来对抗OA的自我调节的基于细胞的植入物 Collins博士独立研究生涯的平台，以及第一个R01的基础。这个价值 平台是互换提供广泛潜在疗法的灵活性。使用这本小说和 灵活的平台，我们将劫持脂肪因子信号传导，以在可调且良好的良好 作为OA的新型再生疗法的控制方式。因为这个IPSC平台可以很容易地容纳 各种细胞类型中感兴趣的目标的编辑和改变，这种疗法的潜力是深远的， 由于许多慢性疾病（癌症，心血管疾病，糖尿病等）与病理炎症有联系 信号。