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Synovial lymphatics and osteoarthritis in aging

衰老过程中的滑膜淋巴管和骨关节炎

基本信息

批准号：
10319543
负责人：
LIANPING XING
金额：
$ 38.42万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10319543
关键词：
Affect Age Aging Alzheimer&apos s Disease Arthritis Attenuated Bioinformatics Bone Spur Bone remodeling Cartilage Cell physiology Cells Chronic Clinical Combined Modality Therapy Data Degenerative polyarthritis Development Disease Drainage procedure Elderly Functional disorder Genes Growth Factor Human Hydroxychloroquine Imaging Device Impairment Inflammation Inflammation Mediators Inflammatory Injections Joints Link Liquid substance Lymphatic Lymphatic Endothelial Cells Lymphatic System Lymphatic function Lysosomes Measures Mediating Mediator of activation protein Molecular Morphology Mus Names Pathogenesis Pathology Pathway interactions Patients Persons Pharmaceutical Preparations Play Post-Translational Protein Processing Predisposition Process Production Proteins Radiolabeled Receptor Protein-Tyrosine Kinases Reporting Research Rheumatoid Arthritis Role Signal Transduction Swelling Synovial Membrane Synovitis System TNFSF11 gene Testing Therapeutic Tissues Tracer Ubiquitination Vascular Endothelial Growth Factor C Vascular Endothelial Growth Factor Receptor-3 age related aged arthropathies base draining lymph node effective therapy experimental study improved inhibitor innovation joint function joint injury lymphatic drainage lymphatic dysfunction lymphatic vessel mouse model novel therapeutics physically handicapped pre-clinical prevent protein expression subchondral bone targeted agent transcriptome

项目摘要

Project Summary/Abstract Osteoarthritis (OA) affects ~35M people in the US and ~250M world-wide, but there is no effective therapy. OA is characterized by cartilage loss, synovial inflammation and subchondral bone remodeling, associated with the accumulation of numerous catabolic mediators and inflammatory cells in the synovial space. How these factors are cleared and if the “clearance” process contributes to the pathogenesis of OA is unknown. Using imaging tools that we developed in past 10 years, we identified a Synovial Lymphatic System (SLS) in mouse joints, the function of which is impaired in joints of mice with age-related OA. Thus, strategies to improve lymphatic function may benefit OA patients. In this application, we hypothesize that 1) aged joints have impaired SLS function and VEGFR3-mediated signaling, accompanied by reduced VEGF-C expression and elevated VEGFR3 degradation; 2) RANKL promotes ubiquitination and lysosomal degradation of VEGFR3 in LECs; and 3) the combination of VEGF-C and agents preventing VEGFR3 degradation improves the SLS and attenuates the development of OA during aging. We will use an age-related OA mouse model to test our hypotheses. In Aim 1, we will determine if the SLS becomes defective during aging and causes OA tissue damage, associated with reduced VEGFR3-mediated signaling in lymphatic endothelial cells. In Aim 2, we will determine the molecular mechanisms whereby VEGFR3 is degraded in aging joints and if a combination of VEGF-C and the inhibition of VEGFR3 degradation prevent OA in aging mice. The results of our study will establish a role for SLS dysfunction in the pathogenesis of OA, and augmentation of SLS functions could be a promising therapeutic approach to prevent or delay age-associated joint damage. This will provide preclinical evidence for agents targeting lymphatic vessels as a potential therapeutic strategy for OA in aging.

项目总结/文摘