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.

目前，仅在美国每年就有超过 360 万名患者遭受骨、关节和软组织的骨科创伤，而且由于人口老龄化和老年人体力活动水平的提高，受伤人数一直在稳步增加。由于车辆和军事伤害，导致骨质流失的严重四肢创伤最近也急剧增加。该应用重点关注骨科创伤的三个主要常见领域：与半月板损伤相关的关节软骨退变、衰老过程中骨折愈合受损以及尚未解决的创伤性节段性骨丢失问题。 骨科骨关节损伤的修复涉及两个关键的相互作用的调节信号通路，即TGF-β/BMP通路和PTH/PTHrP通路。这些途径交互调节间充质干细胞分化为骨和软骨，控制这些组织的表型行为，并构成所提出的 CORT 的基础科学和临床组成部分的统一主题。新数据表明 E3 泛素连接酶、Smurf 1 和 Smurf2 分别通过 BMP 和 TGF-β 信号转导 Smad 的降解来控制细胞表型，以及它们与 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 将涉及一个管理核心和 4 个项目，所有这些都利用研究核心，即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 在衰老骨折愈合中的随机对照试验。 项目 1 评估了 Smurf2 在小鼠模型和人类半月板损伤后导致 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 在老年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 将根据大量的初步临床数据，评估特立帕肽 (PTH) 作为一种加速老年患者功能恢复和低能量骨盆骨折定量放射学愈合的疗法。项目 4 涉及研究 Smurfs 和 PTH 调节 rAAV 基因治疗对小鼠同种异体移植愈合的作用，以及对患者进行新的高分辨率锥形束 CT 扫描的临床试验，以量化同种异体移植与自体移植愈合/血管分布。