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Osteocyte-dependent mechanisms of bone cartilage crosstalk in osteoarthritis

骨关节炎中骨软骨串扰的骨细胞依赖性机制

基本信息

批准号：
10727267
负责人：
Tamara N Alliston
金额：
$ 40.87万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10727267
关键词：
Academia Aging Arthralgia Arthritis Automobile Driving Big Data Biological Biological Markers Biology Candidate Disease Gene Cartilage Chondrocytes Clinical Clinical Research Collaborations Data Data Science Defect Degenerative polyarthritis Development Diagnosis Diagnostic Dimensions Disease Early Diagnosis Face Gene set enrichment analysis Genes Genetic Genetic Markers Genetic Risk Genetic study Genomics Goals Heterogeneity Hip Osteoarthritis Hip region structure Homeostasis Human Human Genetics Human Genome Image In Vitro Individual Industry Joints Knee Knee Osteoarthritis MEPE gene Magnetic Resonance Imaging Molecular Mus Osteocytes Outcome Pain Patients Peptides Persons Pharmaceutical Preparations Phase Phase II Clinical Trials Process Publishing Regulation Research Risk Role Shapes Signal Transduction Subgroup TGFB1 gene Testing Therapeutic Therapeutic Intervention Variant arthropathies biobank bone cartilage degradation clinical predictors clinically relevant cohort deep learning deep learning algorithm differential expression drug development gain of function genetic association genetic variant genome wide association study high risk human imaging imaging biomarker improved innovation interest joint function joint injury loss of function magnetic resonance imaging biomarker mouse model novel novel strategies predictive marker prevent programs skeletal subchondral bone targeted agent targeted treatment trait transcriptome transcriptome sequencing

项目摘要

SUMMARY Cartilage and subchondral bone cooperate to support healthy joint function, and damage to either contributes to osteoarthritis and pain. Nonetheless, the mechanisms by which this cooperation between cartilage and bone occurs remain unclear. Preliminary and published data support the diagnostic and clinical importance of subchondral bone shape in osteoarthritis (OA) progression and pain. Bone shape features, identified by deep learning algorithms, are among the strongest predictive biomarkers for OA. However, a major gap in understanding remains identification of the cellar and molecular mechanisms controlling joint shape. Defining these mechanisms could reveal preventative or therapeutic strategies to protect joints from OA. This team described a new and causal role for osteocytes in OA, such that loss of subchondral bone osteocyte function causes cartilage degeneration and joint shape change. Therefore, with expertise in osteocyte biology, deep learning, and statistical genetics, this team takes an innovative, multi-dimensional approach to identify these mechanisms, as well as genetic and imaging biomarkers that can be used to diagnose early-stage OA when the disease can still be therapeutically modified. This project will test the hypothesis that MRI and genetic markers of joint shape can identify individuals at high risk of OA, and that agents targeting osteocytes can prevent joint shape changes to mitigate OA. Aim 1 will extract genetic factors associated with joint shape traits that predict OA progression and joint pain in the human Osteoarthritis Initiative (OAI) cohort. The function of these genetic factors, including a candidate osteocyte-derived factor that has therapeutic potential in clinical studies, will be examined in Aim 2. This project will impact the identification of genetic correlates to imaging traits that predict clinically relevant OA outcomes in early OA, suggest biological mechanisms driving joint shape change, and highlight these mechanisms as potential targets for OA diagnostics and therapies. Therefore, successful completion of this project could fill a major clinical gap by developing imaging and genetic biomarkers and therapies that can precisely identify and treat subgroups of people at high risk of OA due to joint shape change early enough to prevent severe joint disease.

总结