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Gas-Hedgehog signaling in intramembranous bone formation and expansion

Gas-Hedgehog 信号在膜内骨形成和扩张中的作用

基本信息

批准号：
9191649
负责人：
Yingzi Yang
金额：
$ 47.16万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-05 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9191649
关键词：
Adult Affect Alleles Biological Process Bone Development Bone Diseases Bone Growth Cell physiology Cells Complication Connective Tissue Craniofacial Abnormalities Craniosynostosis Development Disease Dysplasia Embryonic Development Erinaceidae G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs Gases Genes Genetic Growth Hereditary Disease Heterotopic Ossification Human Human Genetics Joints Knowledge Ligands Light Maintenance Malignant Neoplasms McCune-Albright Syndrome Mediating Mesenchymal Stem Cells Mesenchyme Molecular Morphogenesis Motion Mutation Natural regeneration Online Mendelian Inheritance In Man Operative Surgical Procedures Osteoblasts Osteogenesis Osteoporosis Pathologic Pathway interactions Patients Physiological Play Process Proteins Recruitment Activity Regulation Research Research Personnel Role Signal Pathway Signal Transduction Skeletal Muscle Skeletal bone Skeletal system Source Stem cells Subcutaneous Tissue Surgical sutures Testing Tissues Trauma Up-Regulation beta catenin body system bone cell determination cell fate specification cell growth regulation cell type chronic pain craniofacial cranium human disease insight intramembranous bone intramembranous bone formation loss of function mutation mouse model novel osteoblast differentiation osteogenic repaired skeletal skeletal disorder smoothened signaling pathway soft tissue

项目摘要

Gαs-Hedgehog signaling in intramembranous bone formation and expansion Summary The development of a functional skeletal system requires tight spatial and temporal control of osteoblast differentiation and maturation. How osteoblast cells are induced at the outset of bone development is a central question in understanding the organizational principles underpinning a functional skeletal system. Extraskeletal or heterotopic ossification (HO) occurs as a common complication of trauma or in rare genetic disorders and can be disabling and lethal. The precise cellular and molecular mechanisms underlying HO are not clear. Research in our lab has provided insights into the molecular and cellular regulation of bone development and recently we have identified a novel Gαs-Hedgehog (Hh) signaling axis that critically regulates ectopic osteoblast differentiation in progressive osseous heteroplasia (POH). POH is a rare human genetic disease in which HO occurs predominantly through an intramembranous process and progresses from subcutaneous tissue into skeletal muscle and deep connective tissues. POH is caused by inactivating mutations in GNAS that encodes Gαs that transduces signals from G protein coupled receptors (GPCRs). We have found that loss of Gαs function in POH leads to ligand-independent activation of Hh signaling, which in turn induces osteoblast differentiation of mesenchyme cells in soft tissues, whereas activation of Gαs signaling leads to Wnt/β-catenin signaling upregulation and reduced osteoblast differentiation in the human condition of fibrous dysplasia (FD). We have further observed in our preliminary studies that ectopic bone formation and expansion in POH bare cellular and molecular similarities to craniofacial bone development. Here we will build upon our unique perspectives and test our central hypothesis: Hh signaling activation by Gαs inhibition induces osteoblast differentiation during intramembranous bone formation and recruits wild type cells into ectopic bone during progressive ossification in POH. In Specific Aim 1, we will investigate the role of Gαs-regulated Hh signaling during formation and growth of intramembranous bone. In Specific Aim 2, we will extend findings in normal craniofacial bone growth to ectopic bone in POH. We will test our hypothesis that ectopic bone in POH expands by inducing a suture-like tissue where wild type osteogenic mesenchyme stem cells reside. Our proposed studies will provide an unprecedented level of insight in acquired HO and the regulation of osteoblast differentiation under both physiological and pathological conditions. Knowledge gained here from the mouse models of POH will be readily translatable to human diseases such as POH, acquired HO, FD, craniosynostosis and osteoporosis. We anticipate that our findings will have broad significance with respect to cell-fate specification and reprogramming processes during development, repair, and regeneration of many other organ systems where Gαs-Hh and Gαs-Wnt signaling plays a critical role and enhance our understanding of these signaling pathways in human diseases including cancer.

Gαs-Hedgehog 信号在膜内骨形成和扩张中的作用概括功能性骨骼系统的发育需要对成骨细胞进行严格的空间和时间控制分化和成熟。成骨细胞如何在骨骼发育之初被诱导是一个核心问题理解支撑功能性骨骼系统的组织原则的问题。骨骼外或异位骨化 (HO) 作为创伤的常见并发症或罕见的遗传性疾病而发生可能会致残和致命。 HO 的精确细胞和分子机制尚不清楚。我们实验室的研究为骨骼发育和细胞的分子和细胞调节提供了见解。最近我们发现了一个新的 Gαs-Hedgehog (Hh) 信号轴，它可以严格调节异位进行性骨异型增生（POH）中的成骨细胞分化。 POH是一种罕见的人类遗传病 HO 主要通过膜内过程发生并从皮下进展组织分为骨骼肌和深层结缔组织。 POH 是由 GNAS 失活突变引起的编码 Gα，转导来自 G 蛋白偶联受体 (GPCR) 的信号。我们发现损失 POH 中 Gαs 功能的改变导致 Hh 信号的配体独立激活，进而诱导成骨细胞软组织中间充质细胞的分化，而 Gαs 信号传导的激活导致 Wnt/β-catenin 在人类纤维性发育不良 (FD) 情况下，信号传导上调并减少成骨细胞分化。我们在初步研究中进一步观察到，POH 裸露中异位骨的形成和扩张颅面骨发育的细胞和分子相似性。在这里，我们将立足于我们独特的观点并检验我们的中心假设：Gαs 抑制诱导 Hh 信号激活膜内骨形成过程中成骨细胞分化并招募野生型细胞 POH 进行性骨化过程中的异位骨。在具体目标 1 中，我们将研究膜内骨形成和生长过程中 Gαs 调节的 Hh 信号传导。在具体目标 2 中，我们将把正常颅面骨生长的发现扩展到 POH 的异位骨。我们将测试我们的假设 POH 中的异位骨通过诱导缝合样组织而扩展，其中野生型存在成骨间充质干细胞。我们提出的研究将提供前所未有的水平深入了解生理和病理条件下获得性 H2O 和成骨细胞分化的调节状况。从 POH 小鼠模型中获得的知识将很容易转化为人类疾病如POH、获得性HO、FD、颅缝早闭和骨质疏松症。我们预计我们的发现对于细胞命运规范和重编程过程将具有广泛的意义许多其他器官系统的发育、修复和再生，其中 Gαs-Hh 和 Gαs-Wnt 信号传导发挥着关键作用并增强我们对人类疾病中这些信号通路的理解，包括癌症。