Jagged1-based craniofacial bone regeneration

基于Jagged1的颅面骨再生

基本信息

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
项目类别：
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

项目摘要

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.

由于外伤和先天原因，儿童颅面骨丢失很常见。成本归因于目前美国颅面骨缺失修复费用估计高达 5.49 亿美元/年，儿科病例没有再生选择。自体骨移植是唯一的手术方法由于供应有限，需要更换颅面骨并进行翻修手术。骨移植收获需要延长手术时间、住院过夜、髋部疼痛和髋部骨折的风险。当前骨骼成人脊柱手术患者存在再生策略（BMP2）；然而，由于以下原因，不存在针对儿童的 BMP2 对儿童的潜在致癌性。我们的小组确定 Jagged1 是一种潜在的骨再生药物基于从颅神经嵴 (CNC) 删除 Jagged1 后的体外和体内研究的治疗（JAG1CKO）。人类 JAGGED1 突变会导致 Alagille 综合征，该综合征会导致心脏、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。我们的团队最近描述了 Jagged1 在体外和体内的递送通过以下方式诱导矿化和骨化：非规范的 Notch 信号表明 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骨丢失。这该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类骨再生疗法。中心假设是 Jagged1-水凝胶递送可以通过Notch非-诱导人类小儿骨祖细胞（HBO）终末分化形成骨使用体外和体内临床前模型的规范途径。拟议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解决方案。以强有力的初步数据为指导，包括新颖的非规范数据途径，该假设将通过追求两个具体目标来检验：1）工程师 Jagged1 呈现水凝胶在体外通过 Notch 非规范信号传导诱导儿科 HBO 形成骨； 2）体内能力测试 Jagged1 水凝胶在颅面骨丢失的临床前动物模型中再生骨。在目标 1 中，我们将设计一种合成水凝胶来呈现 Jagged1，然后阻断典型的 Notch 信号来测试和描述 HBO 通过 Jagged1 非规范矿化的最佳细胞指导线索途径。在目标 2 中，我们将测试优化的 Jagged1-水凝胶在体内诱导骨形成的能力在小鼠颅面创伤性骨丢失模型中使用 HBO 细胞并诱导间充质干细胞在体内临床前动物模型中诱导骨。拟议的研究具有创新性，因为我们将开发一种针对 Notch 非典型途径的新型 Jagged1-水凝胶疗法并测试 Jagged1- 使用临床前模型的水凝胶疗法。拟议的研究意义重大，因为预计开发颅面骨丢失疗法的第一步，与颅面骨和长骨修复相关。