Treatment and Mechanisms of Diabetic Fracture Healing

项目说明/摘要 骨折愈合对于糖尿病患者来说是一个重大的健康问题，尽管有胰岛素的供应。 策略 由于成本、疗效和副作用的考虑，提高骨折愈合的方法还不够成熟。 初步数据显示，转录因子FOXO1在软骨细胞或 成骨细胞完全修复糖尿病受损骨折愈合的组织学测量，通过MicroCT或 机械测试。我们还确定了特定血统的纤毛丢失，仅限于软骨细胞或 成骨细胞，干扰骨折愈合，模拟糖尿病骨折愈合。基于这些令人兴奋的数据 我们已经设想了一种应用，专注于FOXO1和初级纤毛在软骨细胞和 成骨细胞是糖尿病患者骨折愈合不良的重要因素。因此，拟议的研究 将检验糖尿病导致FOXO1上调和随之而来的下调和丢失的假设 纤毛，进而导致激活软骨细胞/成骨细胞所需的细胞特异性信号的丢失 从而导致骨折愈合不足。为了解决这一假设的治疗益处，我们 已经开发出一种纳米纤维水凝胶，可以控制释放一种胰岛素样生长因子-1模拟物，称为 NFH-IGF。有两个具体目标。目标1将确定FOXO1是否抑制纤毛发生和下游 糖尿病骨折中激活软骨细胞和成骨细胞修复反应所需的信号通路 治愈。具体的机制将使用新开发的细胞功能技术和小鼠进行测试 靶向缺失IFT80以抑制纤毛发生，缺失FOXO1或双缺失FOXO1 IFT80。目标 2将进一步开发一种具有IGF-1活性的模拟物纳米纤维水凝胶的可控释放的新型装置。 胰岛素样生长因子(NFH-IGF)。目的是确定NFH-IGF治疗是否改善T1 DM和T2 DM糖尿病 骨折愈合。机制研究将确定NFH-IGF是否下调FOXO1和上调FOXO1 纤毛在软骨细胞和成骨细胞中增强细胞内信号通路，刺激这些细胞。我们 预计拟议的研究不仅将导致对纤毛在糖尿病骨折中的作用的新认识 治愈，但也导致了一种用于治疗T1 DM和T2 DM的新型辅助治疗工具的开发 纳米纤维水凝胶-IGF配方。

Project Description/Abstract Fracture healing is a significant health issue for patients with diabetes despite the availability of insulin. Strategies to improve fracture healing are underdeveloped due to concerns of costs, effectiveness and side-effects. Preliminary data demonstrate that lineage specific deletion of the transcription factor FOXO1 in chondrocytes or osteoblasts completely rescues diabetes impaired fracture healing measured histologically, by microCT or mechanical testing. We also determined that lineage specific loss of cilia, restricted to chondrocytes or osteoblasts, interferes with fracture healing and mimics diabetic fracture healing. Based on these exciting data we have conceived an application focusing on the role of FOXO1 and primary cilia in chondrocytes and osteoblasts as important contributing factors to deficient fracture healing in diabetics. Thus, the proposed studies will test the hypothesis that diabetes results in upregulation of FOXO1 and concomitant downregulation and loss of cilia, which in turn causes a loss of cell specific signaling needed to activate chondrocytes/osteoblasts and consequentially leading to deficient fracture healing. To address the therapeutic benefits of this hypothesis we have developed a nanofiber hydrogel with controlled release of an insulin-like growth factor-1 mimetic, called NFH-IGF. There are two Specific Aims. Aim 1 will determine if FOXO1 suppresses ciliogenesis and downstream signaling pathways needed to activate healing responses in chondrocytes and osteoblasts in diabetic fracture healing. Specific mechanisms will be tested using the newly developed CyTOF technology and mice with targeted deletions of IFT80 to inhibit ciliogenesis, deletion of FOXO1 or double deletion of FOXO1+IFT80. Aim 2 will further develop a novel device with controlled release of a mimetic with IGF-1 activity, nanofiber hydrogel- IGF (NFH-IGF). The goal is to determine whether NFH-IGF treatment improves T1DM and T2DM diabetic fracture healing. Mechanistic studies will determine whether NFH-IGF downregulates FOXO1 and upregulates cilia in chondrocytes and osteoblasts to enhance intracellular signaling pathways that stimulate these cells. We anticipate that proposed studies will not only result in new knowledge about the role of cilia in diabetic fracture healing but also result in the development in a novel therapeutic aid for the treatment of T1DM and T2DM using nanofiber hydrogel-IGF formulations.