Discoidin domain receptor 2, a novel regulator of bone regeneration

Discoidin 结构域受体 2，骨再生的新型调节剂

基本信息

批准号：
9806949
负责人：
Renny Theodore Franceschi
金额：
$ 23.4万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9806949
关键词：
Adenoviruses Allografting Animals Area Autologous Transplantation Binding Bone Regeneration Bone Tissue Calvaria Cephalic Collagen Collagen Fibril Collagen Receptors Collagen Type I Congenital Abnormality Coupled Coupling Data Defect Development Dwarfism ECM receptor Enterobacteria phage P1 Cre recombinase Exhibits Extracellular Matrix Fibrillar Collagen Fibronectins Fracture Future Genetic Human Implant Integrin Binding Integrins Knock-out Marrow Measures Methods Microspheres Modeling Mus Natural regeneration Neoplasms Operative Surgical Procedures Osteoblasts Osteogenesis Outcome Peptides Periodontal Diseases Phenotype Procedures Receptor Activation Refractory Role Shapes Signal Transduction Site Stem cells Surface Testing Therapeutic Tibial Fractures Tissue Engineering Trauma Work alveolar bone base bone bone cell bone loss cortical bone craniofacial disability discoidin domain receptor 2 discoidin receptor gain of function healing implantation in vivo in vivo regeneration loss of function loss of function mutation nanofiber novel osteoblast differentiation overexpression peptidomimetics poly-L-lactic acid progenitor public health relevance receptor scaffold skeletal skeletal regeneration subcutaneous substantia spongiosa success

项目摘要

Bone loss caused by trauma, neoplasia, congenital defects or periodontal disease is a major cause of disability and human suffering. The limitations of current surgical approaches to treating bone loss have stimulated the development of tissue engineering (TE) strategies for bone regeneration involving a variety of osteoinductive biodegradable scaffolds. In one approach, TE scaffolds were developed containing peptides that mimic extracellular matrix molecules such as collagen. These peptides bind integrin receptors on the surface of skeletal progenitor cells. However, progenitors also interact with collagen via discoidin domain receptor 2 (DDR2), an understudied but important collagen receptor that is essential for bone formation. Our preliminary studies shown DDR2 to also be essential for regeneration of calvarial sub-critical-size defects and tibial fractures. This demonstrates a novel role for DDR2 in bone regeneration and suggests that DDR2-based therapeutics could be a new class of bone regeneration agents. To this end, a triple-helical peptide comprising the DDR binding domain of collagen binds/activates DDR2 and stimulates osteoblast differentiation. Based on these exciting data, we propose the following hypothesis: DDR2 is a critical factor for bone regeneration; stimulating its activity either by regulating its levels or activity using scaffold containing DDR2-binding peptides will positively stimulate bone regeneration. DDR2 stimulates regeneration by functioning together with collagen-binding integrins to induce osteoblast differentiation in skeletal progenitor cells. Studies will develop this exciting new area by achieving the following aims: 1. Establish the requirement for DDR2 in bone regeneration. Gain and loss-of-function approaches will be used to evaluate the requirement for DDR2 in craniofacial regeneration. 2. Develop and evaluate scaffolds containing Ddr2 and integrin-activating peptides in bone regeneration. The feasibility of using DDR2-binding peptides alone and together with integrin-binding peptides in nanofibrous hollow microsphere TE scaffolds will be assessed in a craniofacial regeneration model. Expected outcomes include: 1) demonstration of a functional role for DDR2 in skeletal regeneration in vivo, 2) determine if there is cross-talk between DDR2 and integrin-activating peptides during osteoblast differentiation, 3) complete "proof-of-principle" studies showing the value of DDR2-activating scaffolds for bone TE applications. Studies will support future projects aimed at developing DDR2-based therapeutics.

由创伤，肿瘤，先天性缺陷或牙周疾病引起的骨质流失是残疾和人类苦难。当前手术方法治疗骨质流失的局限性已有刺激了骨骼再生组织工程（TE）策略的发展，涉及多种骨诱导可生物降解的支架。在一种方法中，开发了包含肽的脚手架模仿细胞外基质分子，例如胶原蛋白。这些肽结合整合素受体在骨骼祖细胞的表面。但是，祖细胞也通过盘状蛋白结构域与胶原蛋白相互作用受体2（DDR2），一种研究但重要的胶原蛋白受体，对骨形成至关重要。我们的初步研究表明，DDR2对于钙化亚临界大小缺陷的再生也至关重要。胫骨骨折。这证明了DDR2在骨再生中的新作用，并表明基于DDR2 治疗药物可能是新的骨再生剂。为此，三螺旋肽包括胶原蛋白的DDR结合结构域结合/激活DDR2并刺激成骨细胞分化。基于这些令人兴奋的数据，我们提出以下假设：DDR2是骨再生的关键因素。刺激它的通过使用含有DDR2结合肽的支架来调节其水平或活动的活性会积极刺激骨骼再生。 DDR2通过与胶原结合整合素一起运行到诱导骨骼祖细胞中的成骨细胞分化。研究将通过实现以下目标来发展这个令人兴奋的新领域： 1。确定骨再生中DDR2的要求。获得和功能丧失方法将是用于评估颅面再生中DDR2的需求。 2。在骨再生中开发和评估含有DDR2和整合素激活肽的支架。单独使用DDR2结合肽并与整合素结合肽一起使用的可行性将在颅面再生模型中评估纳米纤维空心微球Te支架。预期结果包括：1）DDR2在骨骼再生中的功能作用的演示体内，2）确定在成骨细胞中DDR2和整联蛋白激活肽之间是否存在串扰分化，3）完整的“原理证明”研究，显示了DDR2激活支架的价值骨骼应用。研究将支持旨在开发基于DDR2的治疗剂的未来项目。