Jagged1-based craniofacial bone regeneration

基于Jagged1的颅面骨再生

• 批准号: 10665048
• 负责人: Steven L Goudy
• 金额: $ 47.66万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-13 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10665048
• 关键词: Adult; Alagille Syndrome; Animal Model; Animals; Autologous; BMP2 gene; Biliary; Binding; Bone Development; Bone Injury; Bone Marrow; Bone Regeneration; Bone Tissue; Bone Transplantation; Calvaria; Cardiac; Cell Density; Cells; Cephalic; Child; Childhood; Clinical; Complex; Cues; Data; Defect; Engineering; Ethylenes; Future; Genes; Glycols; Goals; Harvest; Hip Fractures; Hip Pain; Hip region structure; Histology; Hospitals; Human; Hydrogels; Immune; In Vitro; Inflammation; Life; Ligands; Maleimides; Measures; Mediating; Mesenchymal Stem Cells; Modeling; Morbidity - disease rate; Mus; Mutation; Neural Crest; Notch Signaling Pathway; Operative Surgical Procedures; Organ Transplantation; Oryctolagus cuniculus; Osteoblasts; Osteogenesis; Outcome; Pathway interactions; Patients; Phenocopy; Phenotype; Physiologic Ossification; Pre-Clinical Model; Proteomics; Publishing; Reporting; Research; Risk; Role; Safety; Second Look Surgery; Signal Pathway; Signal Transduction; Spine surgery; System; Testing; Time; Tissue Engineering; Tissues; Trauma; Work; arm; biomechanical test; bone; bone cell; bone loss; bone repair; carcinogenicity; clinically relevant; cost; craniofacial; craniofacial bone; craniofacial repair; craniofacial structure; craniofacial tissue; cytokine; in vivo; in vivo evaluation; innovation; long bone; mineralization; mouse model; notch protein; novel; osteogenic; pediatric patients; pre-clinical; preclinical study; progenitor; receptor; regenerative; regenerative approach; regenerative therapy; stem cells; targeted treatment; therapy development; tissue reconstruction; tissue regeneration; transcriptome sequencing; translational impact

Craniofacial bone loss in children is common due to traumatic and congenital causes. Costs attributed to just the repair of craniofacial bone loss in the US currently is estimated to be up to $549 million/year, and there is no regenerative option for pediatric cases. Autologous bone graft harvest is the only surgical approach to replace craniofacial bone and revision surgeries are necessary due to the limited supply. Bone graft harvest requires prolonged operative time, overnight stay in the hospital, hip pain and risk of hip fracture. Current bone regenerative strategies exist for adult spine surgery patients (BMP2); however none exist for children due to potential carcinogenicity of BMP2 in children. Our group identified Jagged1 as a potential bone regenerative therapy based on in vitro and in vivo studies following deletion of Jagged1 from the cranial neural crest (CNC) (JAG1CKO). Human mutations in JAGGED1 cause Alagille syndrome which has cardiac, biliary and craniofacial bone loss phenotypes and our model is a phenocopy of Alagille craniofacial bone loss. Our team recently described that Jagged1 delivery in vitro and in vivo induces mineralization and ossification through non-canonical Notch signaling suggesting that Jagged1 therapy is a potential bone regenerative strategy. Our long-term goal is to develop bone regenerative approaches to treat craniofacial bone loss in children. The overall objective in this application is to engineer, characterize and test a Jagged1-hydrogel as pre-clinical data to develop human bone regenerative therapies. The central hypothesis is that Jagged1-hydrogel delivery can induce human pediatric bone progenitors (HBO) to terminally differentiate to form bone through a Notch non- canonical pathway using in vitro and in vivo pre-clinical models. The rationale for the proposed research is that the development of bone regenerative Jagged1 osteoinductive hydrogels is the first step towards a novel bone tissue engineering solution for children. Guided by strong preliminary data, including a novel non-canonical pathway, the hypothesis will be tested by pursuing two specific aims: 1) Engineer Jagged1-presenting hydrogel to induce pediatric HBO to form bone through Notch non-canonical signaling in vitro; 2) Test the in vivo ability of Jagged1 hydrogels to regenerate bone in a pre-clinical animal model of craniofacial bone loss. In Aim 1 we will engineer a synthetic hydrogel to present Jagged1, and then block canonical Notch signaling to test and characterize the optimal cell-instructive cues for HBOs to mineralize through the Jagged1 non-canonical pathway. In Aim 2 we will test the ability of optimized Jagged1-hydrogels in vivo to induce bone formation using HBO cells in a murine craniofacial traumatic bone loss model and induce mesenchymal stem cells to induce bone in an in vivo pre-clinical animal model. The proposed research is innovative in that we will develop a novel Jagged1-hydrogel therapy targeting the Notch non-canonical pathway and test the Jagged1- hydrogel therapy using pre-clinical models. The proposed research is significant because it is expected to the first step to develop therapies for craniofacial bone loss, and is relevant to craniofacial and long bone repair.

儿童颅面骨丢失是一种常见的外伤性和先天性原因。成本归因于 目前，美国修复颅面骨丢失的费用估计高达5.49亿美元/年，还有 对于儿科病例没有再生的选择。自体骨移植是唯一的手术治疗方法。 由于供应有限，更换颅面骨和翻修手术是必要的。植骨收获 需要较长的手术时间，在医院过夜，髋部疼痛和髋部骨折的风险。当前骨骼 有成人脊柱手术患者(BMP2)的再生策略；但由于以下原因，儿童没有再生策略 骨形态发生蛋白2对儿童的潜在致癌性。我们的小组确认Jagged1是一种潜在的骨再生细胞 脑神经脊区Jagged1基因缺失后的体内外治疗研究 (JAG1CKO)。人类Jagged1基因突变导致Alagille综合征，该综合征具有心脏、胆道和 颅面骨丢失表型，我们的模型是Alagille颅面骨丢失的表型。我们队 最近报道了Jagged1在体外和体内的传递通过以下途径诱导矿化和成骨 非典型Notch信号提示Jagged1疗法是一种潜在的骨再生策略。我们的 长期目标是开发骨再生方法来治疗儿童颅面部骨丢失。这个 这项应用的总体目标是设计、表征和测试Jagged1-水凝胶作为临床前数据 开发人骨再生疗法。中心假设是Jagged1-水凝胶可以 诱导儿童骨祖细胞终末分化为成骨细胞 使用体外和体内临床前模型的典型路径。建议进行这项研究的理由是 骨再生Jagged1骨诱导水凝胶的开发是迈向新型骨的第一步 儿童组织工程学解决方案。以强劲的初步数据为指导，包括一项新的非规范 这一假说将通过追求两个具体目标来验证：1)工程师Jagged1-呈现水凝胶 体外通过Notch非规范信号诱导儿童HBO成骨；2)体内能力检测 使用Jagged1水凝胶在临床前颅面骨丢失动物模型中再生骨。在目标1中，我们 将设计一种合成水凝胶来呈现Jagged1，然后阻止规范的Notch信号来测试和 描述HBOS通过Jagged1非规范矿化的最佳细胞指导线索 路径。在目标2中，我们将在体内测试优化的Jagged1-水凝胶诱导骨形成的能力 高压氧细胞在小鼠颅面创伤骨丢失模型中的应用及诱导间充质干细胞 在体内临床前动物模型中诱导成骨。拟议的研究是创新的，因为我们将 开发一种针对Notch非典型通路的新型Jagged1-水凝胶疗法，并测试Jagged1- 使用临床前模型的水凝胶疗法。这项拟议的研究具有重要意义，因为它预计将 第一步是开发治疗颅面骨丢失的方法，并与颅面和长骨修复相关。