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: 9757972
• 负责人: Melissa A Kacena
• 金额: $ 61.88万
• 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/9757972
• 关键词: Age; Age-Years; Aging; Angiogenic Factor; Animals; Biomechanics; 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; Fracture Healing; Growth Factor; Histology; Histone Deacetylase; Hospitalization; Impairment; Implant; Injury; Knock-out; 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; X-Ray Computed Tomography; age effect; age related; aged; aging population; angiogenesis; anti aging; base; bone; bone aging; bone healing; bone loss; bone mass; cohort; cytokine; healing; implantation; improved; individualized medicine; interest; mRNA Expression; mortality; mouse model; musculoskeletal injury; novel; novel therapeutic intervention; older patient; overexpression; prevent; repaired; 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.

项目概要 衰老是骨折的主要危险因素。 65岁以上人口占美国总人口的13% 人口，但占因肌肉骨骼损伤住院的 50% 以上。骨折是首要的 老年患者的损伤类型，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能力较低和 血管生成受损。内皮集落形成细胞 (ECFC) 直接参与 血管生成和血管生成。因此，ECFC 数量和/或功能的减少可能是一个主要因素。 老年患者骨折修复失败的驱动因素。为了检查是否可以挽救受损的血管生成 may sufficiently enhance bone healing in the aged population, this proposal will dissect the contribution of 血管生成因子，并评估新型骨愈合剂通过刺激作用的程度 内皮细胞（EC）在小鼠骨老化愈合模型中的功能。我们已经在老鼠批评中展示了 大小缺陷（CSD）模型，当胶原蛋白支架植入年轻的 ECFC 时，再生速度加快 被植入缺损处。我们还表明，主要的巨核细胞生长因子血小板生成素 (TPO)，可以增强小鼠 CSD 的愈合，同时增加 EC。 TPO 还可治愈大鼠 CSD 和猪。我们最近的数据显示 Sirtuin-1 (Sirt1)（一种 NAD+ III 类组蛋白脱乙酰酶）的 mRNA 水平 与老年 EC 相比，年轻的 CD45-CD31+ EC 中的抗衰老作用显着更高。 此外，与成年小鼠相比，年轻小鼠的骨折再生中Sirt1 mRNA显着增加。 老老鼠。此外，新的初步数据表明，SRT1720（sirt1 激活剂）治疗可改善骨骼 康复。基于这些观察，我们假设衰老过程中骨愈合可以通过以下方式得到增强： 通过直接植入 ECFC 或通过 TPO 刺激 EC 来改善血管生成 SRT1720。在目标 1 中，我们将评估年轻或年老 ECFC 作为骨再生疗法的用途。在目标 2 中， 我们将评估TPO或SRT1720对骨愈合的治疗效果，并剖析EC的贡献 在老年小鼠中发出这种反应的信号。这些目标的成功实现将决定 衰老过程中内皮细胞的退化是与年龄相关的骨愈合能力下降的原因 过程。此外，使用两种已知针对 EC 的不同骨愈合剂，我们将确定年龄特异性 EC 刺激的差异以及这些差异如何影响骨折修复过程。