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：
10685932
负责人：
PAUL B YU
金额：
$ 36.74万
依托单位：
MASSACHUSETTS GENERAL 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 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10685932
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 Cellular biology Characteristics Chemicals Collaborations Complex Connective Tissue Degenerative Disorder Disease Engineering Exhibits Family Fascia Funding Genetic Genetic Models Goals Hematology Heterotopic Ossification Homeostasis Human Hybrids Immobilization Immunology In Vitro Individual Infiltration Inflammation Injury Intervention Intramuscular Joints Knock-in Knock-in Mouse Knowledge Lead Ligaments Ligands Malignant Neoplasms Maps 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 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 analytical tool bone bone morphogenetic protein receptor type I bone morphogenetic protein receptors cancer cell cell type combinatorial drug development effective therapy efficacy evaluation emerging adult 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 pharmacologic 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.

项目摘要/摘要异位骨化（HO），骨骼肌和柔软的异位内侧软骨骨的形成组织是关节固定和疼痛发病率的重要原因。精确的机制负责HO是不知道的；但是，它与创伤，炎症和生物力学应力表明损伤修复和稳态的过程。我们有探索了HO，纤维浮肿的单基因原因的基本机制由骨形态发生蛋白（BMP）I型激活突变引起的Progressiva（FOP）受体ALK2，而创伤引起的HO似乎由ALK2，ALK3调节，并可能受到可能的调节 ALK6。 FOP和获得的HO形式具有不适当的BMP信号传导的共同机制，但是，解释BMP信号以调节骨化与组织的方式再生仍然不完全理解。组合BMP/TGFB的差距很大信号转导指定多能谱系中的各种功能和细胞命运。解决这些机械差距是使用人类的创新化学生物学平台设计的创新化学生物学平台由CRISPR/CAS9技术编辑的衍生MSC，结合了新型BMP/TGF-B 从活跃的NCATS-TRND合作中确定的药理学探测器。这个平台将允许单个配体和受体信号传导的明确映射以及下游对在不过表达的人类细胞系统中的MSC可塑性。该测定提供了一个高度的平台将在NCATS-TRND与合作者一起执行的吞吐量屏幕以机械识别 ALK2，ALK3和ALK6的新型调节剂。最后，从中鉴定出的见解和候选分子这些研究将在有条件的FOP型鼠标模型中得到验证，并在真实的创伤和炎症引起的HO的小鼠模型。这些研究将提供关键的工具和深入了解BMP信号通路如何有助于病理组织重塑肌肉骨骼和退化性疾病，以及在更广泛的疾病中与衰老，炎症和代谢应激有关。新测定技术，工具这项工作将产生化合物和可翻译的见解许多其他面向疾病的研究领域。