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.

项目总结 年龄是骨折的主要危险因素。65岁以上的人口占美国总人口的13% 人口，但占50%的肌肉骨骼损伤入院人数。骨折是主要的 老年患者的损伤类型和年龄的增加是骨折愈合受损的危险因素。延迟 老年患者骨折愈合的原因是间充质干细胞分化能力降低和 血管生成/血管生成受损。内皮细胞集落形成细胞(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原因 老年患者骨折修复失败的驱动因素。为了检查是否挽救受损的血管生成 可以充分促进老年人口的骨愈合，这项建议将剖析 血管生成因子，并评估新型骨愈合药物通过刺激发挥作用的程度 内皮细胞(EC)在随年龄增长而愈合的小鼠模型中发挥作用。我们已经在一只老鼠的危急时刻展示了 大小缺损(CSD)模型，胶原支架种植年轻ECFCs可加速再生 都被植入了缺损处。我们还表明，主要的巨核细胞生长因子，血小板生成素 (TPO)，可促进CSD小鼠的愈合并伴随内皮细胞的增加。TPO还可以治愈大鼠的慢性阻塞性肺疾病 还有猪。我们最近的数据显示，NAD+III类组蛋白去乙酰基酶Sirtuin-1(Sirt1)的mRNA水平 具有抗衰老作用，年轻的CD45-CD31+内皮细胞明显高于老年内皮细胞。 此外，幼年小鼠骨折愈合过程中Sirt1基因的表达水平显著高于正常对照组。 老老鼠。此外，新的初步数据显示，SRT1720(SIRT1激活剂)治疗改善了骨骼 治愈。基于这些观察，我们假设在衰老过程中可以通过以下方式促进骨骼愈合 直接植入内皮细胞或TPO或TPO刺激内皮细胞促进血管生成 SRT1720。在目标1中，我们将评估年轻或年老的ECFC作为骨再生疗法的使用。在目标2中， 我们将评估TPO或SRT1720在骨愈合方面的疗效，并剖析EC的贡献 在衰老的小鼠中发出这种反应的信号。这些目标的成功实现将决定到什么程度 衰老过程中内皮细胞的退变是导致骨愈合的增龄性下降的原因 进程。此外，使用目标内皮细胞已知的两种不同的骨愈合试剂，我们将确定特定的年龄 EC刺激的差异以及这些差异如何影响骨折修复过程。