Translating molecular signal pathways to orthopaedic trauma care

将分子信号通路转化为骨科创伤护理

• 批准号: 7139583
• 负责人: RANDY N ROSIER
• 金额: $ 157.39万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-15 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7139583
• 关键词: aging; bone; clinical research; homologous transplantation; human; injury; joints; model; role; tissues; trauma

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.

描述（由申请人提供）：骨骼，关节和软组织的骨外科创伤目前每年仅在美国涉及超过360万患者，并且由于人口老龄化和老年人的体育活动水平增加，伤害的数量一直在稳步增加。由于车辆和军事伤害，有问题的严重肢体创伤因骨质流失而造成骨质流失。该应用集中于骨外科创伤的三个主要公共区域：与半月板损伤相关的关节软骨变性，衰老中的骨折愈合受损以及尚未解决的创伤性节段性骨骼损失问题。 骨科骨和关节的修复涉及两个关键的相互作用的调节信号par。 创伤，即TGF-BETA/BMP途径和PTH/PTHRP途径。这些途径可以在互动地调节间充质干细胞分化为骨骼和软骨，控制这些组织的表型行为，并构成了拟议Cort的基础科学和临床成分的统一主题。新数据分别通过BMP和TGF-BETA信号SMAD​​S降解来控制E3泛素连接酶，SMURF 1和SMURF2，及其与PTH和炎症细胞因子的调节相互作用，构成了基础科学和临床项目目标的基础。 Cort将涉及一个行政核心和4个项目，所有这些都利用了研究核心，这是分子和解剖成像核心。所有项目均涉及损伤和修复动物模型的转化方法，以及3项临床研究，包括衰老中断裂愈合中PTH的RCT。项目1评估了蓝精灵在鼠模型和人类中半月板损伤后导致OA的分子事件中的作用。将研究与人类中功能和定量MRI结果的相关性。 项目2将定义蓝精和PTH在衰老小鼠中断裂模型中的作用，以确定使用PTH在刺激衰老患者刺激骨折愈合中使用的分子基础。项目3将基于急剧的初步临床数据，将评估Teriparatide（PTH）作为一种疗程的加速疗法，以加速衰老患者的低能量骨盆骨折的定量射线照相愈合。项目4涉及研究蓝精灵和对小鼠同种异体愈合的基因治疗的PTH调节的作用，以及针对患者进行新的高分辨率锥束CT扫描的临床试验，以量化同种异体移植物与自体移植愈合/血管性的临床试验。