Hedgehog pathway in periosteum-mediated repair and regeneration

Hedgehog 通路在骨膜介导的修复和再生中的作用

• 批准号: 7825685
• 负责人: XINPING ZHANG
• 金额: $ 21.77万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7825685
• 关键词: Address; Adipocytes; Adult; Agonist; Allografting; Area; Autologous Transplantation; Automobile Driving; Biomechanics; Bone Regeneration; Bone Transplantation; Cell Differentiation process; Cells; Chondrocytes; Clinical; Critical Pathways; Data; Defect; ENG gene; Embryo; Engraftment; Erinaceidae; Excision; Gene Deletion; Gene Expression; Goals; Healed; Histologic; Histology; Impaired wound healing; In Vitro; Life; Limb Development; Mediating; Mesenchymal; Mesenchymal Stem Cells; Modeling; Molecular; Mus; Musculoskeletal; N-terminal; Natural regeneration; Osseointegration; Osteoblasts; Osteogenesis; Pathway interactions; Patients; Peptides; Periosteum; Play; Regenerative Medicine; Role; Series; Signal Transduction; Site; Skin Tissue; Tamoxifen; Testing; Therapeutic; Transplantation; United States National Institutes of Health; allogenic bone transplantation; angiogenesis; base; bone; bone morphogenetic protein 2; gain of function; graft healing; healing; high risk; human SMO protein; implantation; improved; in vivo; insight; loss of function; mineralization; mouse model; novel strategies; osteogenic; progenitor; purmorphamine; receptor; recombinase; reconstruction; repaired; response; small molecule; smoothened signaling pathway; stage-specific embryonic antigen 4; stem cell population; success; tissue regeneration

DESCRIPTION (provided by applicant): This current application addresses Regenerative Medicine (11) as the broad challenge area. Specifically, this application seeks further understanding of molecular pathways that control expansion and differentiation of periosteal mesenchymal stem cells (MSCs) during cortical bone graft healing and incorporation. The proposal fits into the following challenge topics: 11-AR-101*: Musculoskeletal and Skin Tissue Regeneration. Periosteum plays key role in repair and regeneration. Autograft is superior to synthetics or allograft in reconstruction largely due to the presence of mesenchymal stem cells (MSCs) residing in periosteum. Currently the molecular pathways that regulate proliferation and differentiation of periosteal MSCs at the site of healing are poorly understood. In response to the challenge topics identified by NIH, we propose a series of novel approaches to define a critical pathway, namely the Hedgehog pathway, in periosteum-mediated bone graft repair and incorporation. Hh pathway has been shown to be critically involved in embryonic limb development. However, its role in adult bone repair remains elusive. Our preliminary data demonstrates that Hh pathway still operates in adult periosteal repair. Activation of Hh pathway markedly enhances the differentiation of MSCs isolated from autograft periosteum and induces bone formation in vivo. We therefore hypothesize that activation of Hh pathway plays key roles in osseointegration of cortical bone grafts via stimulating osteogenic differentiation of periosteal MSCs. Engraftment of Hh activated periosteal MSCs at the site of compromised periosteum will enhance cortical bone graft healing and incorporation. In Aim1, we will define the role of Hh-loss-of function in periosteum-dependent cortical bone graft incorporation by targeted deletion of Smoothened, the receptor that tranduces all Hh signaling in periosteal MSCs. In Aim2, we will define the role of Hh-gain-of function in cortical bone allograft incorporation by engraftment of Hh-activated periosteal MSCs at the site of compromised periosteum. The proposed study will bring new insights into the understanding of molecular control of periosteum-initiated bone graft incorporation, further offering a potential pathway-targeted therapy for improved healing at the site of compromised periosteum. The long-term goal of our project is to identify critical pathways and mechanisms for bone repair and reconstruction. Specifically in this project we propose to examine the role of Hh pathway in repair and regeneration.

描述（由申请人提供）：本申请将再生医学（11）作为广泛的挑战领域。具体地，本申请寻求进一步理解在皮质骨移植物愈合和并入期间控制骨膜间充质干细胞（MSC）的扩增和分化的分子途径。该提案符合以下挑战主题：11-AR-101*：肌肉骨骼和皮肤组织再生。骨膜在修复和再生中起着关键作用。自体骨在重建方面上级人工骨或同种异体骨，这主要是由于骨膜中存在间充质干细胞（MSCs）。目前，调控愈合部位骨膜间充质干细胞增殖和分化的分子途径知之甚少。针对NIH确定的挑战主题，我们提出了一系列新的方法来定义骨膜介导的骨移植修复和整合中的关键途径，即刺猬途径。Hh通路在胚胎肢体发育中起着重要作用。然而，它在成人骨修复中的作用仍然难以捉摸。我们的初步数据表明，Hh通路仍然在成人骨膜修复。Hh通路的激活可显著增强自体骨膜分离的MSCs的分化，并在体内诱导成骨。因此，我们推测Hh通路的激活通过刺激骨膜间充质干细胞的成骨分化在皮质骨移植物的骨整合中起关键作用。Hh活化的骨膜MSC在受损骨膜部位的植入将促进皮质骨移植物的愈合和结合。在Aim 1中，我们将通过靶向删除Smoothened（在骨膜MSC中传导所有Hh信号的受体）来确定Hh功能丧失在骨膜依赖性皮质骨移植物掺入中的作用。在Aim 2中，我们将通过将Hh激活的骨膜MSC植入受损的骨膜部位来定义Hh功能获得在皮质骨同种异体移植物结合中的作用。拟议的研究将为理解骨膜引发的骨移植物掺入的分子控制带来新的见解，进一步提供潜在的路径靶向治疗，以改善受损骨膜部位的愈合。我们项目的长期目标是确定骨修复和重建的关键途径和机制。具体来说，在这个项目中，我们建议检查Hh通路在修复和再生中的作用。