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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。归因于