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：
10757487
负责人：
PAUL B YU
金额：
$ 29.24万
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/10757487
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.

项目概要/摘要异位骨化（HO），骨骼肌和软组织中异位软骨内骨的形成组织，是关节不活动和疼痛发病的重要原因。精确的机制负责 HO 的人员未知；然而，它与创伤、炎症和生物力学应激表明损伤修复和体内平衡紊乱的过程。我们有探索了 HO 的单基因原因，即骨化性纤维发育不良的潜在机制进行性 (FOP)，由 I 型骨形态发生蛋白 (BMP) 的激活突变引起受体 ALK2，而创伤诱导的 HO 似乎受 ALK2、ALK3 和潜在的调节 ALK6。 FOP 和获得性 HO 共享不适当的 BMP 信号传导的共同机制，但 BMP 信号被解释来调节骨化与组织的方式再生仍然不完全清楚。 BMP/TGFb 的组合方式存在显着差距信号转导指定多能谱系中的不同功能和细胞命运。致地址针对这些机械缺陷，我们利用人类设计了一个创新的化学生物学平台衍生的 MSC，经过 CRISPR/Cas9 技术编辑，结合新型 BMP/TGF-b 通过活跃的 NCATS-TRND 合作鉴定出药理学探针。该平台将允许个体配体和受体信号传导的明确映射，以及对下游的影响非过度表达的人类细胞系统中的 MSC 可塑性。该测定提供了一个高水平的平台将与 NCATS-TRND 的合作者一起进行吞吐量筛选，以机械地识别 ALK2、ALK3 和 ALK6 的新型调节剂。最后，见解和候选分子确定这些研究将在 FOP 的条件敲入小鼠模型和真实的 FOP 模型中得到验证创伤和炎症诱导的 HO 小鼠模型。这些研究将提供关键工具和深入了解 BMP 信号通路如何促进病理组织重塑肌肉骨骼和退行性疾病，以及 H2O 更广泛的病症与衰老、炎症和代谢应激有关。新的检测技术、工具这项工作的结果将产生化合物和可转化的见解，这些见解将与许多其他以疾病为导向的研究领域。

项目成果

期刊论文数量（25）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Application of in vitro Drug Metabolism Studies in Chemical Structure Optimization for the Treatment of Fibrodysplasia Ossificans Progressiva (FOP).

体外药物代谢研究在治疗进行性骨化性纤维发育不良 (FOP) 的化学结构优化中的应用。

DOI：
发表时间：
2019
期刊：
影响因子：
0
作者：
Padilha, Elias C;Wang, Jianyao;Kerns, Ed;Lee, Arthur;Huang, Wenwei;Jiang, Jian;McKew, John;Mutlib, Abdul;Peccinini, Rosangela G;Yu, Paul B;Sanderson, Philip;Xu, Xin
通讯作者：
Xu, Xin

Fibrodysplasia Ossificans Progressiva: What Have We Achieved and Where Are We Now? Follow-up to the 2015 Lorentz Workshop.

进行性骨化性纤维发育不良：我们取得了什么成就，现在处于什么位置？

DOI：
发表时间：
2021
期刊：
影响因子：
0
作者：
de Ruiter, Ruben D;Smilde, Bernard J;Pals, Gerard;Bravenboer, Nathalie;Knaus, Petra;Schoenmaker, Ton;Botman, Esmée;Sánchez;Pacifici, Maurizio;Pignolo, Robert J;Shore, Eileen M;van Egmond, Marjolein;Van Oosterwyck, Hans;Kapla
通讯作者：
Kapla

BMP Ligand Trap ALK3-Fc Attenuates Osteogenesis and Heterotopic Ossification in Blast-Related Lower Extremity Trauma.

BMP 配体陷阱 ALK3-Fc 减弱爆炸相关下肢创伤中的成骨和异位骨化。

DOI：
发表时间：
2021
期刊：
影响因子：
4
作者：
Strong, Amy L;Spreadborough, Philip J;Dey, Devaveena;Yang, Peiran;Li, Shuli;Lee, Arthur;Haskins, Ryan M;Grimm, Patrick D;Kumar, Ravi;Bradley, Matthew J;Yu, Paul B;Levi, Benjamin;Davis, Thomas A
通讯作者：
Davis, Thomas A

In Search of the Second Hit in Pulmonary Arterial Hypertension.

寻找肺动脉高压的第二次打击。