ALTERING THE IMMUNE LANDSCAPE TO AUGMENT BONE REGENERATION

改变免疫景观以增强骨再生

• 批准号: 10727797
• 负责人: Daniel Alge
• 金额: $ 36.91万
• 依托单位: TEXAS ENGINEERING EXPERIMENT STATION
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10727797
• 关键词: Adult; Aftercare; Antigens; BMP2 gene; Benchmarking; Biocompatible Materials; Bone Injury; Bone Regeneration; Bone Tissue; Calvaria; Cells; Centers for Disease Control and Prevention (U.S.); Child; Clinical; Collagen; Control Groups; Data; Defect; Disease; Dose; Exhibits; Experimental Models; Female; Femur; Gender; Hemagglutinin; Hematoxylin and Eosin Staining Method; Histology; Hydrogels; Immune; Immune response; Immune system; Immunize; Immunohistochemistry; Immunologic Memory; Immunologic Tests; Immunology; Immunotherapy; Implant; Influenza; Influenza Hemagglutinin; Injury; Modeling; Mus; Nanoporous; Natural regeneration; Nature; Osteogenesis; Peptides; Play; Population; Porifera; Porosity; Regenerative engineering; Regenerative response; Research; Role; Site; Structure; Testing; Therapeutic; Time; Tissue Engineering; Tissues; Trichrome stain method; Vaccinated; Vaccination; Vaccine Antigen; Vaccines; Work; adaptive immunity; biomaterial compatibility; bone; bone healing; cell motility; cell regeneration; clinically relevant; controlled release; design; ethylene glycol; experimental study; healing; hydrogel scaffold; immune cell infiltrate; immunoengineering; improved; improved outcome; in vivo; influenza virus vaccine; injured; innovation; male; memory recognition; novel; particle; porous hydrogel; recombinant human bone morphogenetic protein-2; recruit; regenerative; regenerative therapy; scaffold; seasonal influenza; single-cell RNA sequencing; synthetic peptide; tomography; transcriptomics; translational potential; unvaccinated; vaccine evaluation

PROJECT SUMMARY The overarching hypothesis of this project is that bone regeneration can be enhanced by exploiting vaccination status and recruiting adaptive immunity to the injury site through controlled release of an antigen. To test this hypothesis, the general approach in this project will be to immunize mice and then perform in vivo bone tissue engineering studies to test the impact of antigen delivery from the scaffold on bone formation and the immune response. The mice will specifically be vaccinated against influenza due to high annual vaccine coverage in the U.S. population, and influenza-derived hemagglutinin (HAG) peptide will be delivered from implanted scaffolds. Testing will be performed in mice using two experimental models, calvarial defects and femoral defects. In both models, the bone defects will be treated with hydrogel scaffolds releasing HAG peptide alone or in combination with therapeutic or sub-therapeutic doses of recombinant human bone morphogenetic protein-2 (BMP-2). All treatments will be duplicated in an unvaccinated control group using both male and female mice to test for gender effects. There are two Specific Aims. Aim 1 is focused on evaluating bone formation and defect regeneration, which will be evaluated at 3 weeks and 6 weeks after treatment by microcomputed tomography analysis and histology. The results will be benchmarked against defect treatment with a therapeutic dose of BMP-2 delivered from a collagen sponge, which will serve as a clinical control treatment. Aim 2 is focused on evaluating the effects of HAG peptide delivery on the immune response. Immune cell infiltration in the regenerating defects will be evaluated at 3 weeks and 6 weeks after treatment by immunostaining. In addition, transcriptomic changes will be evaluated 1 week after treatment by single-cell RNA sequencing. If successful, this project will lead to novel regenerative immunotherapies with high translational potential.

项目摘要 该项目的总体假设是可以通过利用来增强骨骼再生 通过控制释放的疫苗接种状况和招募对伤害部位的适应性免疫 抗原。为了检验这一假设，该项目的一般方法将是免疫小鼠， 然后进行体内骨组织工程研究，以测试从 骨形成和免疫反应的支架。小鼠将特别接种疫苗 由于美国人口中年度疫苗的覆盖范围高，反对流感，并衍生了流感 血凝素（hag）肽将从植入的支架中输送。测试将在 小鼠使用两个实验模型，钙化缺陷和股骨缺陷。在这两种模型中，骨头 缺陷将用单独释放hag肽的水凝胶支架处理或与 重组人骨形态发生蛋白2（BMP-2）的治疗或亚治疗剂量。 所有治疗方法都将在未接种的对照组中重复，使用雄性和雌性小鼠 测试性别影响。有两个具体的目标。 AIM 1专注于评估骨形成 和缺陷再生，将在治疗后3周和6周通过 微型层析成像分析和组织学。结果将针对缺陷进行基准测试 用从胶原蛋白海绵输送的治疗剂量的BMP-2治疗，将作为一个 临床控制治疗。 AIM 2的重点是评估hag肽递送对 免疫反应。再生缺陷中的免疫细胞浸润将在3周时评估 通过免疫染色治疗后6周。此外，将评估转录组的变化 单细胞RNA测序治疗后1周。如果成功，这个项目将导致新颖 具有高转化潜力的再生免疫疗法。