Angiogenic Therapy: Novel Approaches to Enhance Bone Regeneration in Aging

血管生成疗法：增强衰老过程中骨再生的新方法

• 批准号: 10356802
• 负责人: Melissa A Kacena
• 金额: $ 55.13万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10356802
• 关键词: Age; Age-Years; Aging; Angiogenic Factor; Animals; Blood Vessels; Blood capillaries; Bone Marrow; Bone Regeneration; Bone callus; Cell Count; Cell Lineage; Cell physiology; Cells; Collagen; Data; Defect; Endothelial Cells; Endothelium; Family suidae; Fluorescence-Activated Cell Sorting; Fracture; Growth Factor; Histology; Histone Deacetylase; Hospitalization; Impairment; Implant; Injury; MPL gene; Measures; Megakaryocytes; Membrane; Mesenchymal Stem Cells; Messenger RNA; Modeling; Morbidity - disease rate; Mus; Natural regeneration; Older Population; Operative Surgical Procedures; Orthopedics; Osteoblasts; PECAM1 gene; PTPRC gene; Persons; Pharmacology; Pilot Projects; Population; Process; Rattus; Risk Factors; SIRT1 gene; Signal Transduction; Tamoxifen; Testing; Therapeutic; Thrombopoietin; Treatment Efficacy; Work; age effect; age related; aged; aging population; angiogenesis; anti aging; base; biomechanical test; bone; bone aging; bone fracture repair; bone healing; bone loss; bone mass; cohort; collagen scaffold; conditional knockout; cytokine; healing; implantation; improved; individualized medicine; interest; mRNA Expression; microCT; mortality; mouse model; musculoskeletal injury; novel; novel therapeutic intervention; older patient; overexpression; prevent; regenerative therapy; response; scaffold; selective expression; stem cell differentiation; synthetic polymer Bioplex; vasculogenesis

PROJECT SUMMARY Aging is the dominant risk factor for fracture. Persons over 65 years of age account for 13% of the total US population, but represent > 50% of hospital admissions with a musculoskeletal injury. Fractures are the primary injury type among older patients, and increased age is a risk factor for impaired fracture healing. Delayed fracture healing in elderly patients results from a lower capacity for mesenchymal stem cell differentiation and impaired angiogenesis/vasculogenesis. Endothelial colony forming cells (ECFCs) are directly involved in angiogenesis and vasculogenesis. Thus, the decrease in number and/or function of ECFCs may be a major driver for failed fracture repair in elderly patients. In order to examine whether rescue of impaired angiogenesis may sufficiently enhance bone healing in the aged population, this proposal will dissect the contribution of angiogenesis factors, and evaluate the extent to which novel bone healing agents operate via stimulating endothelial cell (EC) function in a mouse model of bone healing with aging. We have shown in a rat critical sized defect (CSD) model, regeneration was accelerated when collagen scaffolds seeded with young ECFCs were implanted within the defect. We also show that the main megakaryocyte growth factor, thrombopoietin (TPO), can augment CSD healing in mice with concomitant increase in ECs. TPO can also heal CSDs in rats and pigs. Our recent data show that mRNA levels of Sirtuin-1 (Sirt1), an NAD+ class III histone deacetylase with anti-aging effects, were significantly higher in young CD45-CD31+ ECs as compared to old ECs. Additionally, Sirt1 mRNA significantly increased in the fracture regenerate of young mice compared to that of old mice. Further, new preliminary data showed that treatment with SRT1720 (sirt1 activator) improved bone healing. Based on these observations, we hypothesize that bone healing can be enhanced in aging by improvement of angiogenesis via direct implantation of ECFCs or through stimulation of ECs by TPO or SRT1720. In Aim 1, we will assess the use of young or old ECFCs as a bone regeneration therapy. In Aim 2, we will assess the therapeutic efficacy of TPO or SRT1720 on bone healing, and dissect the contribution of EC signaling to this response in aged mice. Successful accomplishment of these Aims will determine the degree to which the degeneration of ECs during aging is responsible for the age-related decline in the bone healing process. Additionally, using two distinct bone healing agents known to target ECs, we will identify age-specific differences in EC stimulation and how these differences influence the fracture repair process.

项目摘要 衰老是骨折的主要危险因素。 65岁以上的人占美国总数的13％ 人口，但占肌肉骨骼损伤的医院入院率> 50％。骨折是主要的 老年患者的损伤类型和年龄增加是骨折愈合受损的危险因素。延迟 老年患者的骨折愈合是由于间充质干细胞分化和 血管生成/血管生成受损。内皮菌落形成细胞（ECFC）直接参与 血管生成和血管生成。因此，ECFC的数量和/或功能的减少可能是主要的 老年患者骨折修复失败的驱动器。为了检查拯救受损的血管生成 可以充分增强老年人口的骨骼愈合，该提议将剖析 血管生成因子，并评估新型骨骼愈合剂通过刺激起作用的程度 内皮细胞（EC）在骨骼愈合的小鼠模型中的功能。我们已经在大鼠关键 大小缺陷（CSD）模型，当胶原蛋白支架与年轻ECFC播种时，再生加速 被植入缺陷。我们还表明，主要的巨核细胞生长因子，血栓蛋白 （TPO），可以增强小鼠的CSD愈合，而EC伴随增加。 TPO也可以治愈大鼠的CSD 和猪。我们最近的数据表明，sirtuin-1（SIRT1）的mRNA水平，NAD+ III类脱乙酰基酶 与旧EC相比，具有抗衰老效应的年轻CD45-CD31+ EC中的抗衰老作用明显更高。 此外，与 老鼠。此外，新的初步数据表明，SRT1720（SIRT1激活剂）的治疗改善了骨骼 康复。基于这些观察结果，我们假设可以通过 通过直接植入ECFC或通过TPO或TPO刺激EC来改善血管生成 SRT1720。在AIM 1中，我们将评估年轻或老年ECFC作为骨再生疗法的使用。在AIM 2中， 我们将评估TPO或SRT1720对骨骼愈合的治疗功效，并剖析EC的贡献 向年龄小鼠的这种反应发出信号。成功完成这些目标将决定 衰老期间EC的退化是导致骨骼愈合与年龄相关的下降 过程。此外，使用已知EC的两种不同的骨愈合剂，我们将确定年龄特定的 EC刺激的差异以及这些差异如何影响断裂修复过程。