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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.

儿童颅面骨丢失是常见的，由于创伤和先天性原因。成本归因于目前，美国颅面骨缺损的修复估计高达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，需要进行颅面骨置换和翻修手术。植骨采集需要延长手术时间，在医院过夜，髋关节疼痛和髋关节骨折的风险。当前骨骼成人脊柱手术患者存在再生策略（BMP 2）;但由于 BMP 2对儿童的潜在致癌性。我们的研究小组将Jagged 1鉴定为潜在的骨再生因子，基于从颅神经嵴（CNC）中删除Jagged 1后的体外和体内研究的治疗（JAG1CKO）. JAGGED 1的人类突变导致Alagille综合征，其具有心脏、胆道和我们的模型是Alagille颅面骨丢失的表型。我们的团队最近描述了Jagged 1在体外和体内的递送通过以下途径诱导矿化和骨化：非经典Notch信号转导表明Jagged 1疗法是一种潜在的骨再生策略。我们长期目标是开发骨再生方法来治疗儿童颅面骨丢失。的本申请的总体目标是设计、表征和测试锯齿状1-水凝胶作为临床前数据开发人类骨骼再生疗法中心假设是锯齿状1-水凝胶递送可以诱导人小儿骨祖细胞（HBO）终末分化形成骨，使用体外和体内临床前模型的典型途径。拟议研究的理由是，骨再生Jagged 1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。在强有力的初步数据的指导下，包括一个新的非典型的途径，该假设将通过追求两个具体目标进行测试：1）工程锯齿1-呈递水凝胶体外通过Notch非经典信号诱导小儿HBO成骨; 2）体内实验的Jagged 1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，将设计一种合成水凝胶来呈现Jagged 1，然后阻断经典的Notch信号传导，表征HBO通过锯齿状1非典型矿化的最佳细胞指导线索通路在目标2中，我们将测试优化的锯齿状1-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。这项研究是创新的，我们将开发一种针对Notch非经典途径的新型Jagged 1-水凝胶疗法，并测试Jagged 1- 使用临床前模型的水凝胶疗法。这项研究意义重大，因为它有望这是开发颅面骨丢失治疗方法的第一步，与颅面和长骨修复相关。