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

• 批准号: 9977158
• 负责人: Renny Theodore Franceschi
• 金额: $ 19.5万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 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/9977158
• 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; 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; stem cells; subcutaneous; substantia spongiosa; success

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、肿瘤形成、先天性缺陷或牙周病引起的骨丢失是牙周病的主要原因。 残疾和人类痛苦。目前治疗骨丢失的手术方法的局限性 刺激了骨再生的组织工程（TE）策略的发展，涉及各种 骨诱导生物可降解支架。在一种方法中，开发了含有肽的TE支架， 模拟细胞外基质分子如胶原蛋白。这些肽结合细胞表面的整合素受体 骨骼祖细胞的表面。然而，祖细胞也通过盘状结构域与胶原蛋白相互作用 受体2（DDR2），一种研究不足但重要的胶原蛋白受体，对骨形成至关重要。我们 初步研究显示DDR2对于颅骨亚临界大小缺损的再生也是必需的， 胫骨骨折这证明了DDR2在骨再生中的新作用，并表明基于DDR2的 治疗剂可能是一类新的骨再生剂。为此，提供了一种三螺旋肽，其包含 胶原的DDR结合结构域结合/激活DDR2并刺激成骨细胞分化。基于 基于这些令人兴奋的数据，我们提出了以下假设：DDR2是骨再生的关键因素;刺激其 通过调节其水平或使用含有DDR2结合肽的支架的活性将积极地 刺激骨骼再生。DDR2通过与胶原结合整合素一起发挥作用来刺激再生， 诱导骨骼祖细胞成骨细胞分化。 研究将通过实现以下目标来开发这一令人兴奋的新领域： 1.确定骨再生中DDR2的要求。功能增益和功能丧失方法将 用于评估颅面再生对DDR2的需求。 2.开发和评估含有Ddr2和整合素激活肽的骨再生支架。 单独使用DDR2结合肽和与整联蛋白结合肽一起使用DDR2结合肽的可行性研究。 将在颅面再生模型中评估纳米纤维中空微球TE支架。 预期的结果包括：1）证明DDR2在骨骼再生中的功能作用， 体内，2）确定在成骨细胞生长过程中DDR2和整合素活化肽之间是否存在串扰， 3）完整的“原理验证”研究，显示DDR2活化支架对于 骨TE应用。研究将支持未来旨在开发基于DDR2的治疗方法的项目。