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The Role of Fat in Osteoarthritis

脂肪在骨关节炎中的作用

基本信息

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
项目类别：
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

项目摘要

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.

项目总结