Role of estrogen and mechanobiology on meniscal regeneration

雌激素和力学生物学对半月板再生的作用

• 批准号: 10242610
• 负责人: Jennifer Lindsey Robinson
• 金额: $ 13.9万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-15 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10242610
• 关键词: 3-Dimensional; Adult; Behavior; Biochemical; Biological; Biomechanics; Cartilage; Cells; Centers of Research Excellence; Cues; Data; Degenerative polyarthritis; Development; Disease Pathway; Disease Progression; Environment; Estradiol; Estrogen Receptor alpha; Estrogen Therapy; Estrogens; Extracellular Matrix; Failure; Feasibility Studies; Female; Fibrocartilages; Funding; Future; Genes; Genetic Transcription; Gonadal Steroid Hormones; Grant; Health; Health Care Costs; Homeostasis; Individual; Joints; Knee Injuries; Knee Osteoarthritis; Knee joint; Knock-out; Knockout Mice; Mechanics; Mediating; Meniscus structure of joint; Microfabrication; Microfluidics; Modeling; Modulus; Molecular Analysis; Mus; Natural regeneration; Pain; Pathway interactions; Patients; Phenotype; Physiological; Placebos; Play; Production; RNA; Research; Risk; Role; Signal Transduction; Structure; Tissues; Up-Regulation; Work; cartilage degradation; cell behavior; disability; effective therapy; experience; genome sequencing; in vivo; macromolecule; male; mechanotransduction; migration; repaired; three-dimensional modeling; transcriptome

The long-term objective of the proposed work is to determine the role of estrogen and the mechanical microenvironment on meniscus health and regeneration to reduce osteoarthritis onset and progression. Knee osteoarthritis is a major cause of global disability resulting in over $6,000 in annual healthcare costs per patient. Meniscal tears are the most prevalent intra-articular knee injury and pose significant risk in the development of OA. Recent studies have shown that adult males experience greater tear complexity and have a reduced repair rate compared to females suggesting that sex hormones, including estrogen, may play a role in protecting the menisci from tear and promote repair. However, the differential role of estrogen and the mechanical environment on regional transcriptional changes, cell phenotype, and mechanotransduction have not been determined. Thus, this proposal aims to tackle this overarching question by evaluating the effect of estrogen treatment and substrate modulus on meniscal fibrochondrocytes in 2D and 3D. The hypothesis that physiological estrogen treatment and substrate modulus will promote an increase in meniscal extracellular matrix production and regeneration will be investigated in the following aims: 1) Elucidate the role of estrogen via estrogen receptor alpha on meniscal fibrochondrocyte proliferation and extracellular matrix production 2) Determine impact of substrate modulus on fibrochondrocyte migration, mechanotransduction, and phenotype in the presence of estrogen in 2D and 3D Deciphering the mechanism by which estrogen promotes meniscal fibrocartilage homeostasis is a vital first step in patient-specific repair and regeneration to reduce osteoarthritis progression and alleviate the corresponding pain and discomfort.

拟议工作的长期目标是确定雌激素和机械性激素的作用。 微环境对半月板的健康和再生，以减少骨关节炎的发生和发展。膝 骨关节炎是全球残疾的一个主要原因，导致每年每个人的医疗费用超过6,000美元 有耐心的。半月板撕裂是最常见的膝关节内损伤，对 办公自动化的发展。最近的研究表明，成年男性经历更大的泪水复杂性和 与女性相比，修复率较低，这表明包括雌激素在内的性激素可能起到了作用 起到保护半月板免受撕裂和促进修复的作用。然而，雌激素和雌激素的不同作用 机械环境对区域转录变化、细胞表型和机械转导的影响 还没有确定。因此，本提案旨在通过评估 雌激素处理和底物模数对2D和3D半月板纤维软骨细胞的影响。这个 生理雌激素治疗和底物模数将促进半月板增加的假说 细胞外基质的产生和再生将在以下目标中进行研究： 1)阐明雌激素通过雌激素受体α在半月板纤维软骨细胞增殖中的作用 细胞外基质的产生 2)确定底物模数对纤维软骨细胞迁移、机械转导和 2D和3D中雌激素存在时的表型 破译雌激素促进半月板纤维软骨稳态的机制是至关重要的第一步 介入患者特有的修复和再生，以减缓骨关节炎的进展和缓解 相应的疼痛和不适。