Treatment and Mechanisms of Diabetic Fracture Healing

项目描述/文摘

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.