Translating molecular signal pathways to orthopaedic trauma care

描述（由申请人提供）：目前仅在美国，每年就有超过360万例骨、关节和软组织的骨科创伤患者，由于人口老龄化和老年人体力活动水平的增加，受伤人数一直在稳步增加。由于车辆和军事伤害，有问题的严重肢体创伤伴骨丢失最近也急剧增加。该应用程序集中在骨科创伤的三个主要常见领域：与关节损伤相关的关节软骨退变，老化中的骨折愈合受损，以及创伤性节段性骨丢失的未解决问题。 在骨科骨关节修复过程中，有两条重要的相互作用的调控信号通路 创伤，即TGF-β/BMP途径和PTH/PTHrP途径。这些途径相互作用地调节间充质干细胞向骨和软骨的分化，控制这些组织的表型行为，并构成了所提出的CORT的基础科学和临床组成部分的统一主题。新的数据表明E3泛素连接酶Smurf 1和Smurf 2分别通过降解BMP和TGF-β信号Smads控制细胞表型，以及它们与PTH和炎性细胞因子的调节相互作用，形成了基础科学和临床项目目标的基础。CORT将涉及一个管理核心和4个项目，所有这些项目都利用研究核心，一个分子和解剖成像核心。所有项目都涉及损伤和修复动物模型的转化方法，以及3项临床研究，包括PTH在老年骨折愈合中的RCT。项目1评估了Smurf 2在小鼠模型和人类中导致关节损伤后OA的分子事件中的作用。将研究与人类功能和定量MRI结果的相关性。 项目2将定义Smurfs和PTH在老龄小鼠骨折模型中的作用，以确定使用PTH刺激老年患者骨折愈合的分子基础。项目3将根据引人注目的初步临床数据，评估特立帕肽（PTH）作为加速老年患者低能量骨盆骨折功能恢复和定量放射学愈合的治疗方法。项目4涉及研究Smurfs和PTH对rAAV基因治疗在小鼠同种异体移植物愈合中的作用，以及在患者中进行新的高分辨率锥形束CT扫描以量化同种异体移植物与自体移植物愈合/血管分布的临床试验。

DESCRIPTION (provided by applicant): Orthopaedic trauma to bones, joints, and soft tissues currently involves over 3.6 million patients each year in the U.S. alone, and the number of injuries has been steadily increasing due to the aging population and increased levels of physical activity in older individuals. Problematic severe extremity trauma with bone loss has also recently increased dramatically due to vehicular and military injuries. This application focuses on three major common areas of orthopaedic trauma: articular cartilage degeneration associated with meniscal injuries, impaired fracture healing in the aging, and the unsolved problem of traumatic segmental bone loss. Two critical interacting regulatory signal pathyways are involved in the repair of orthopaedic bone and joint trauma, namely the TGF-beta/BMP pathway and the PTH/PTHrP pathway. These pathways interactively regulate differentiation of mesenchymal stem cells into bone and cartilage, control the phenotypic behavior of these tissues, and constitute a unifying theme for both the basic science and clinical components of th proposed CORT. New data implicating E3 ubiquitin ligases, Smurf 1 and Smurf2, in the control of cell phenotype through degradation of BMP and TGF-beta signaling Smads, respectively, and their regulatory interactions with PTH and inflammatory cytokines, form the basis for the basic science and clinical Project aims. The CORT will involve an Administrative Core and 4 Projects, all of which utilize the research core, a Molecular and Anatomic Imaging Core. All projects involve translational approaches with animal models of injury and repair, as well as 3 clinical studies, including an RCT of PTH in fracture healing in the aging. Project 1 evaluates the role of Smurf2 in molecular events leading to OA after meniscal injury in a murine model, and in humans. Correlation with functional and quantitative MRI outcomes in humans will be studied. Project 2 will define the role of Smurfs and PTH in a fracture model in aging mice, to determine the molecular basis for use of PTH in stimulating fracture healing in aging patients. Project 3 will evaluate teriparatide (PTH) as a therapy for acceleration of return to function and quantitative radiographic healing of low energy pelvic fractures in aging patients, based on dramatic preliminary clinical data. Project 4 involves study of the role of Smurfs and PTH modulation of gene therapy with rAAV for allograft healing in mice, and a clinical trial of new high resolution cone beam CT scans in patients to quantify allograft vs autograft healing/vascularity.