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: 7891430
• 负责人: RANDY N ROSIER
• 金额: $ 137.45万
• 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/7891430
• 关键词: Translating; molecular; signal; pathways; orthopaedic

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.

骨、关节和软组织的骨科创伤目前仅在美国每年就涉及超过360万患者，并且由于人口老龄化和老年人体力活动水平的增加，损伤的数量一直在稳步增加。由于车辆和军事伤害，严重的四肢创伤和骨质流失最近也急剧增加。本应用程序着重于骨科创伤的三个主要常见领域：半月板损伤相关的关节软骨退变，老化中骨折愈合受损，以及未解决的创伤性节段性骨丢失问题。