Treatment and Mechanisms of Diabetic Fracture Healing

糖尿病骨折愈合的治疗及机制

• 批准号: 10595341
• 负责人: DANA T GRAVES
• 金额: $ 47.03万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10595341
• 关键词: Address; Affect; Age; Animals; Breathing; Cells; Chondrocytes; Cilia; Data; Development; Devices; Diabetes Mellitus; Diabetic mouse; Disease; Dislocations; Down-Regulation; Effectiveness; Event; FOXO1A gene; Formulation; Fracture; Future; Genes; Goals; Health; Histologic; Human; Hydrogels; Impairment; In Vitro; Injectable; Injections; Insulin; Insulin-Dependent Diabetes Mellitus; Insulin-Like Growth Factor I; Jeune syndrome; Knowledge; Link; Measures; Mechanics; Metabolic; Molecular; Mus; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Osteoblasts; Osteogenesis; Pathogenesis; Pathologic; Patients; Physiology; Pseudarthrosis; Role; Short Rib-Polydactyly Syndrome; Signal Pathway; Signal Transduction; Technology; Testing; Therapeutic; Up-Regulation; bone fracture repair; ciliopathy; cilium biogenesis; controlled release; cost; diabetic; diabetic patient; engineering design; experimental study; healing; high risk; improved; in vivo; microCT; mimetics; nanofiber; novel; novel therapeutics; preclinical study; repaired; response; side effect; tool; transcription factor

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.

项目描述/摘要 尽管有胰岛素，但骨折愈合对于糖尿病患者来说是一个重要的健康问题。 策略 由于成本、有效性和副作用的考虑，改善骨折愈合的方法尚未开发。 初步数据表明，软骨细胞中转录因子 FOXO1 的谱系特异性缺失或 成骨细胞完全挽救糖尿病损伤的骨折愈合（通过 microCT 或组织学测量） 机械测试。我们还确定了纤毛的谱系特异性损失，仅限于软骨细胞或 成骨细胞，干扰骨折愈合并模仿糖尿病骨折愈合。基于这些令人兴奋的数据 我们构思了一个应用程序，重点关注 FOXO1 和初级纤毛在软骨细胞中的作用， 成骨细胞是糖尿病患者骨折愈合不良的重要影响因素。因此，拟议的研究 将检验糖尿病导致 FOXO1 上调以及随之而来的下调和缺失的假设 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传导丧失， 从而导致骨折愈合不良。为了解决这一假设的治疗益处，我们 开发了一种纳米纤维水凝胶，可控制释放胰岛素样生长因子 1 模拟物，称为 NFH-IGF。有两个具体目标。目标 1 将确定 FOXO1 是否抑制纤毛发生及其下游 糖尿病骨折中激活软骨细胞和成骨细胞愈合反应所需的信号通路 康复。具体机制将使用新开发的 CyTOF 技术和小鼠进行测试 靶向删除 IFT80 以抑制纤毛发生、删除 FOXO1 或双重删除 FOXO1+IFT80。目的 2将进一步开发一种新型装置，可控制释放具有IGF-1活性的模拟物，纳米纤维水凝胶- IGF（NFH-IGF）。目标是确定 NFH-IGF 治疗是否可以改善 T1DM 和 T2DM 糖尿病 骨折愈合。机制研究将确定 NFH-IGF 是否下调 FOXO1 并上调 软骨细胞和成骨细胞中的纤毛增强刺激这些细胞的细胞内信号传导途径。我们 预计拟议的研究不仅会产生关于纤毛在糖尿病骨折中的作用的新知识 治愈，而且还导致开发出一种用于治疗 T1DM 和 T2DM 的新型治疗辅助剂 纳米纤维水凝胶-IGF 配方。