Wnt Signaling for Improved Fracture Healing

Wnt 信号传导促进骨折愈合

• 批准号: 8053811
• 负责人: Tripti Gaur
• 金额: $ 7.82万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8053811
• 关键词: Ablation; Acceleration; Accidents; Acetates; Address; Adverse effects; Age; Aging; Agonist; Athletic Injuries; Baby Booms; Biological; Bone callus; Bone remodeling; Calcified; Cartilage; Cells; Chemicals; Chondrocytes; Clinical; Clinical Research; Complementary DNA; Complex; Data; Diabetes Mellitus; Disease; Equilibrium; Event; Foundations; Fracture; Fracture Healing; Frequencies; Future; Generations; Genetic; Goals; Healed; Hematoma; Histologic; Hypertrophy; Immunohistochemistry; In Situ; In Situ Hybridization; Lead; Life; Ligands; Malignant Neoplasms; Maps; Mature Bone; Mechanics; Mesenchymal; Mesenchymal Stem Cells; Molecular; Mus; Orthopedics; Osteoblasts; Osteogenesis; Osteoporosis; Pathway interactions; Patients; Phenotype; Phorbol; Phorbols; Play; Process; Recruitment Activity; Regulation; Reporting; Role; Sampling; Series; Signal Pathway; Signal Transduction; Site; Staging; Structure; Surgeon; Testing; Therapeutic; Therapeutic Agents; Therapeutic Uses; Time; Tissues; Transgenic Mice; Translating; Translations; Trauma; United States; Up-Regulation; Wound Healing; Youth; age related; base; bone; bone loss; bone mass; bone quality; defined contribution; falls; healing; improved; inhibitor/antagonist; mouse model; osteoblast differentiation; regenerative; repaired; response; skeletal; small molecule

DESCRIPTION (provided by applicant): PROJECT SUMMARY Wnt signaling for improved fracture healing Bone fractures are the most frequent problems observed by orthopedic surgeons all over the world. Fractures are mostly caused by trauma (fall, sports injury, road accidents) in healthy youth. However, age progression or certain diseases e.g. diabetes, cancer, osteoporosis etc, lead to higher frequency of bone fractures which are greatly impaired and result in multiple complications. Several clinical studies as well as transgenic mouse models have shown that induced Wnt signaling pathway can support accelerated bone formation. Ablation of a Wnt antagonist, sFRP1 leads to a high bone mass phenotype in later stages of life. We have shown that young mice without sFRP1 also have increased osteoblast differentiation/bone parameters and hypertrophic cartilage without adverse effects. We postulate that this balanced phenotype in the sFRP1-/- mice is a result of contribution of both canonical as well non-canonical Wnt pathways. Our objective is to examine the role of activated Wnt signaling during fracture healing, and to achieve improved fracture repair. We predict a tight regulation of Wnt signaling and a fine balance between activation of canonical and non-canonical pathways during fracture healing process. Few small molecule compounds have been reported to stimulate both canonical as well as non-canonical Wnt signaling pathways. Using these synthetic compounds to induce Wnt signaling and mimic the phenotype of sFRP1-/- mouse, we expect to translate our findings into therapies to treat fracture patients.

描述（由申请人提供）： 项目摘要Wnt信号改善了骨折治愈骨折的骨折是世界各地骨科医生观察到的最常见问题。骨折主要是由健康青年中的创伤（秋季，运动损伤，道路事故）引起的。但是，年龄的进展或某些疾病，例如糖尿病，癌症，骨质疏松症等，导致骨折的频率较高，这些骨折受到严重损害并导致多种并发症。几项临床研究以及转基因小鼠模型表明，诱导的Wnt信号通路可以支持加速的骨形成。 Wnt拮抗剂的消融，SFRP1在生命的后期导致高骨质量表型。我们已经表明，没有SFRP1的年轻小鼠还增加了成骨细胞分化/骨参数和肥厚性软骨而没有不良反应。我们假设SFRP1 - / - 小鼠中这种平衡的表型是规范和非典型WNT途径的贡献的结果。我们的目标是检查裂缝愈合过程中激活的Wnt信号传导的作用，并进行改善的断裂修复。我们预测Wnt信号的严格调节以及在断裂愈合过程中规范和非统治途径激活之间的良好平衡。据报道，很少有小分子化合物可以刺激规范和非规范Wnt信号通路。使用这些合成化合物诱导Wnt信号传导并模仿SFRP1 - / - 小鼠的表型，我们希望将我们的发现转化为治疗骨折患者的疗法。