GDF-5 Regulation in Intervertebral Disc Degeneration

描述（由申请人提供）：椎间盘退变引起的背痛是西方社会的主要健康问题。目前的治疗旨在获得症状缓解。正在寻求能够停止、延缓或逆转椎间盘退变影响的基于生物学的治疗方法。生长分化因子-5（GDF-5）是关节形成和软骨细胞发育的重要生长因子，缺乏GDF-5会导致椎间盘早期退变，值得深入研究。然而，GDF-5在椎间盘退变中的时间表达是未知的，并且很少有关于GDF-5治疗椎间盘退变的研究。我们假设GDF-5在椎间盘修复中起重要作用，GDF-5治疗退行性椎间盘中代谢受损的细胞可以恢复椎间盘基质和结构。目的1：利用免疫定位和实时荧光定量RT-PCR技术研究GDF-5和细胞外蛋白的表达和分布。GDF-5的表达和椎间盘退变程度之间的相关性将被阐明。该信息对于理解GDF-5在椎间盘退变中的作用是必不可少的，以便做出充分知情的决定，使用GDF-5作为早期椎间盘损伤或退变的治疗剂。在目的2A中，我们将使用GDF-5缺陷小鼠模型，其提供了通过局部校正遗传缺陷来定义GDF-5在IVD修复中的作用的独特机会。我们的研究小组已经对GDF-5缺陷小鼠的椎间盘进行了表征，并显示出与退行性椎间盘相似的组织学和生化异常。我们的体外研究支持GDF-5治疗可以使椎间盘细胞代谢的一些参数正常化的假设。假设区域性GDF-5基因治疗将使GDF-5缺陷小鼠椎间盘的MRI外观、组织学和生物化学正常化。在目的2B中，将使用发育良好的椎间盘退变模型来研究GDF-5疗法除了对GDF-5缺乏诱导的椎间盘退变的治疗效果之外是否将延缓或逆转由其他致病因素诱导的椎间盘退变。如果成功实现有意义的修复，该项目将帮助研究人员在人类椎间盘修复方面取得重大进展。

DESCRIPTION (provided by applicant): Back pain resulting from intervertebral disc degeneration is a major health problem in western societies. Current therapies are aimed at gaining symptomatic relief. The searches for biologically based treatments that can halt, retard or reverse the effects of disc degeneration are being sought. Growth Differentiation Factor-5 (GDF-5), an important growth factor for joint formation and chondrocyte development, deficiency of which would lead to early degeneration of intervertebral disc, deserves a detailed investigation. However, the temporal expression of GDF-5 in disc degeneration is unknown and there are few studies on GDF-5 therapy for disc degeneration. We hypothesize that GDF-5 plays an important role in disc repair and GDF-5 therapy to metabolically impaired cells in degenerative IVD can restore the disc matrix and structure. In Aim 1, we will define temporal expression and distribution of GDF-5 and extracellular proteins with immunolocalization and real-time RT-PCR. Correlation between GDF-5 expression and degree of disc degeneration will be elucidated. This information is essential to understand the role of GDF-5 in disc degeneration in order for a well informed decision to be made to use GDF-5 as a therapeutic agent for early stage disc injury or degeneration, In Aim 2A, we will use the GDF-5 deficient mouse model which provides a unique opportunity to define the role of GDF-5 in IVD repair by local correction of a genetic defect. The discs of the GDF-5 deficient mouse have been characterized by our research group and were shown to have histological and biochemical abnormalities similar to degenerative disc. Our in vitro studies support the hypothesis that GDF-5 therapy can normalize some parameters of disc cell metabolism. It is hypothesized that regional GDF-5 gene therapy will normalize the MRI appearance, histology, and biochemistry of the intervertebral disc in the GDF-5 deficient mouse. In Aim 2B, a well-developed disc degeneration model will be used to investigate whether GDF-5 therapy will retard or reverse disc degeneration that is induced by other pathogenic factors in addition to therapeutic effects on GDF-5 deficiency-induced disc degeneration. If successful in achieving meaningful repair, this project will help investigators make significant strides towards enabling disc repair in humans.