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Molecular and cellular mechanisms of heterotopic ossification

异位骨化的分子和细胞机制

基本信息

批准号：
10238889
负责人：
PAUL B YU
金额：
$ 7.65万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10238889
关键词：
ACVR1 gene Activin Receptor Activins Address Alleles Animal Model Autoimmune Diseases Biological Assay Biology Biomechanics Birth Blood Vessels Bone Morphogenetic Proteins CRISPR/Cas technology Cardiovascular Diseases Cell Differentiation process Cell Line Cell model Cells Characteristics Chemicals Collaborations Complex Connective Tissue Degenerative Disorder Disease Engineering Exhibits Family Fascia Funding Genetic Genetic Models Goals Hematology Heterotopic Ossification Homeostasis Human Hybrids Immunology In Vitro Individual Infiltration Inflammation Injury Intervention Intramuscular Joints Knock-in Knock-in Mouse Knowledge Lead Ligaments Ligands Malignant Neoplasms Mediating Metabolic Diseases Metabolic stress Molecular Morbidity - disease rate Muscle Musculoskeletal Development Musculoskeletal Diseases Mutation National Center for Advancing Translational Sciences Osteogenesis Pain Pathologic Patients Pharmacology Phosphotransferases Physiologic Ossification Population Process Prophylactic treatment Receptor Signaling Resistance Role Signal Pathway Signal Transduction Signaling Protein Skeletal Muscle Specific qualifier value Stress Syndrome System Techniques Technology Tendon structure Testing Tissues Transforming Growth Factor beta Trauma Traumatic injury Type I Activin Receptors Vascular calcification Work activin A activin B analytical tool bone bone morphogenetic protein receptor type I bone morphogenetic protein receptors cancer cell cell type combinatorial drug development effective therapy efficacy evaluation field study high throughput screening induced pluripotent stem cell inhibitor injury and repair innovation insight interstitial iron metabolism kinase inhibitor mouse model mutant neglect neutralizing antibody novel osteogenic prevent progenitor programs progressive myositis ossificans receptor repaired resistance mutation scaffold senescence skeletal abnormality soft tissue stem cells tissue regeneration tool tool development translatable strategy

项目摘要

PROJECT SUMMARY/ABSTRACT Heterotopic ossification (HO), the formation of ectopic endochondral bone in skeletal muscle and soft tissues, is a significant cause of morbidity from joint immobility and pain. The precise mechanisms responsible for HO are not known; however, its association with trauma, inflammation and biomechanical stress suggests a process of disordered injury repair and homeostasis. We have explored the underlying mechanisms of a monogenic cause of HO, fibrodysplasia ossificans progressiva (FOP), caused by activating mutations of the bone morphogenetic protein (BMP) type I receptor ALK2, whereas trauma-induced HO appears to be regulated by ALK2, ALK3 and potentially ALK6. FOP and acquired forms of HO share a common mechanism of inappropriate BMP signaling, but the manner by which BMP signals are interpreted to regulate ossification versus tissue regeneration remain incompletely understood. Significant gaps exist in how combinatorial BMP/TGFb signal transduction specifies diverse functions and cell fates in multipotent lineages. To address these mechanistic gaps, an innovative chemical biology platform has been devised using human- derived MSC that have been edited by CRISPR/Cas9 techniques, combined with a novel BMP/TGF-b pharmacologic probe identified from an active NCATS-TRND collaboration. This platform will permit the unequivocal mapping of individual ligand and receptor signaling, and the downstream impact on MSC plasticity in a non-overexpressed human cell system. This assay provides a platform for a high throughput screen to be performed with collaborators at NCATS-TRND to identify mechanistically novel modulators of ALK2, ALK3 and ALK6. Finally, insights and candidate molecules identified from these studies will be validated in a conditional knock-in mouse model of FOP, and in an authentic mouse model of trauma- and inflammation-induced HO. These studies will provide critical tools and insights into how the BMP signaling pathway contributes to pathologic tissue remodeling in musculoskeletal and degenerative disease, as well as in a broader set of conditions in which HO is associated with senescence, inflammation, and metabolic stress. New assay technologies, tool compounds, and translatable insights will be produced as a result of this work that will be relevant to many other disease-oriented fields of study.

项目总结/文摘