Viscoelastic Properties of Normal and OA Chondrons

正常软骨和 OA 软骨的粘弹性

• 批准号: 10158380
• 负责人: Farshid Guilak
• 金额: $ 53.31万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10158380
• 关键词: 3-Dimensional; Abbreviations; Affect; Apoptosis; Biochemical; Biological; Biomechanics; Biophysics; COL6A3; Cartilage; Cell membrane; Cells; Characteristics; Chondrocyte-like Cell; Chondrocytes; Clustered Regularly Interspaced Short Palindromic Repeats; Collagen Type VI; Complex; DNA Sequence Alteration; Degenerative polyarthritis; Development; Disease; Elements; Environment; Epigenetic Process; Equilibrium; Event; Experimental Models; Extracellular Matrix; Functional disorder; Genes; Genetic Transcription; Genetic Variation; Health; Homeostasis; Human; In Vitro; Injury; Ion Channel; Ions; Joints; Knock-out; Lead; Life Style; Liquid substance; Measurement; Mechanics; Metabolic; Modeling; Molecular; Mutation; Pathologic; Pharmacology; Physical therapy; Physiological; Play; Population; Property; Proteins; Risk; Risk Factors; Role; Secondary to; Signal Transduction; Solid; Structure; System; Techniques; Theoretical model; Tissue Engineering; Tissues; articular cartilage; cartilage matrix protein; causal variant; disease-causing mutation; disorder risk; early onset; exome sequencing; functional loss; genome editing; genome wide association study; genome-wide; in vitro Model; induced pluripotent stem cell; innovation; insight; mechanical load; mechanical properties; mutant; novel; regenerative therapy; response; stem; subchondral bone; transcriptome; viscoelasticity

PROJECT SUMMARY / ABSTRACT Osteoarthritis (OA) is a highly prevalent, disabling degenerative disease of the joints that is characterized by progressive deleterious changes in the articular cartilage, subchondral bone, and other joint tissues. This project will exploit emerging evidence from exome sequencing in a unique selection of (early onset) familial OA cases that resulted in the identification of high impact mutations in COL6A3 likely causal to OA. The mechanism by which such a mutation increases the risk for OA is unclear, partly because there is substantial genetic variation among the population and lifestyle differences that can affect the development of OA. We propose to develop a novel in vitro system for studying the functional effect of identified OA causal variants on the biochemical and mechanical properties of articular cartilage using genome editing of COL6A3 in induced pluripotent stem cells (iPSCs) and cartilage tissue engineering. Type VI collagen plays a critical role in the function of the chondron – the chondrocyte and its surrounding pericellular matrix – which has been shown the regulate the biological and biomechanical environment of chondrocytes in articular cartilage. We will use a combined experimental and theoretical modeling approach to determine how changes in the physicochemical properties of the PCM with COL6A3 mutation influence the mechanical interactions between the chondrocyte and ECM in chondrogenically differentiated iPSCs. We will examine the early signaling events as well as the long-term influence of COL6A3 knockout or mutation on chondrocyte response to loading. Finally, we will examine the effect of the COL6A3 knockout or mutation on the epigenetically controlled changes of the transcriptome of chondrocytes in response to loading. A detailed understanding of these mechanisms will provide critical insight into the development of new pharmacologic, regenerative, or physical therapies for OA.

项目总结/摘要 骨关节炎（OA）是一种高度流行的致残性关节退行性疾病，其特征在于： 关节软骨、软骨下骨和其他关节组织中的进行性有害变化。这 该项目将利用外显子组测序的新证据，在一个独特的选择（早发）家族性OA 导致鉴定出可能导致OA的COL6A3高影响突变的病例。的 这种突变增加OA风险的机制尚不清楚，部分原因是 人群中的遗传变异和生活方式差异可能会影响OA的发展。我们 我建议开发一种新的体外系统，用于研究已鉴定的OA致病变异体对 使用COL6A3基因组编辑的关节软骨的生物化学和机械特性 多能干细胞（iPSC）和软骨组织工程。VI型胶原蛋白在免疫调节中起关键作用。 软骨的功能-软骨细胞及其周围的细胞周基质-这已被证明， 调节关节软骨中软骨细胞的生物学和生物力学环境。我们将使用一个 结合实验和理论建模方法，以确定物理化学 具有COL6A3突变的PCM的性质影响软骨细胞之间的机械相互作用， 和ECM在成软骨分化的iPSC中的作用。我们将研究早期信号事件以及 COL6A3敲除或突变对软骨细胞对负荷反应的长期影响。最后我们将 检查COL6A3敲除或突变对表观遗传学控制的变化的影响， 软骨细胞的转录组响应于负荷。对这些机制的详细了解将 为OA的新药理学、再生或物理疗法的发展提供重要见解。