GDF-5 Regulation in Intervertebral Disc Degeneration

GDF-5 对椎间盘退变的调节

• 批准号: 7474631
• 负责人: XUDONG J. LI
• 金额: $ 7.21万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7474631
• 关键词: Appearance; Back Pain; Biochemical; Biochemistry; Biological Assay; Biologically Based Therapy; Cell Nucleus; Cells; Chondrocytes; Chondrogenesis; Chronic; Collagen Type II; Condition; Development; Disease; Extracellular Matrix Proteins; Extracellular Protein; GDF5 gene; Gene Expression; Genes; Growth Factor; Healed; Health; Histology; Human; In Vitro; Injury; Intervertebral disc structure; Investigation; Joints; Lead; Magnetic Resonance Imaging; Metabolism; Modeling; Molecular; Mus; Mutation; Needles; Play; Process; Production; Proteins; Proteoglycan; Puncture procedure; Radiology Specialty; Regulation; Research; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Role; Societies; Staging; Structure; Symptoms; Therapeutic Agents; Therapeutic Effect; Time; base; gene therapy; growth differentiation factor 5; healing; improved; in vivo; injured; intervertebral disk degeneration; mouse model; protein expression; repaired; research study; size

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.

描述（由申请人提供）：椎间盘退变引起的背痛是西方社会的一个主要健康问题。目前的治疗旨在缓解症状。人们正在寻求基于生物学的治疗方法，以阻止、延缓或逆转椎间盘退变的影响。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，缺乏它会导致椎间盘早期退变，值得详细研究。然而，GDF-5在椎间盘退变中的时间表达尚不清楚，并且GDF-5治疗椎间盘退变的研究也很少。我们假设 GDF-5 在椎间盘修复中发挥重要作用，并且 GDF-5 治疗退行性 IVD 中代谢受损的细胞可以恢复椎间盘基质和结构。在目标 1 中，我们将通过免疫定位和实时 RT-PCR 定义 GDF-5 和细胞外蛋白的时间表达和分布。将阐明 GDF-5 表达与椎间盘退变程度之间的相关性。这些信息对于了解 GDF-5 在椎间盘退变中的作用至关重要，以便做出明智的决定，使用 GDF-5 作为早期椎间盘损伤或退变的治疗剂。在目标 2A 中，我们将使用 GDF-5 缺陷小鼠模型，该模型提供了一个独特的机会，通过局部校正遗传缺陷来定义 GDF-5 在 IVD 修复中的作用。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，并显示其具有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 疗法可以使椎间盘细胞代谢的某些参数正常化的假设。据推测，局部 GDF-5 基因治疗将使 GDF-5 缺陷小鼠的椎间盘 MRI 外观、组织学和生物化学正常化。在目标 2B 中，除了对 GDF-5 缺乏引起的椎间盘退变的治疗效果之外，将使用成熟的椎间盘退变模型来研究 GDF-5 疗法是否会延缓或逆转由其他致病因素引起的椎间盘退变。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。

项目成果

Intervertebral disc degeneration and ectopic bone formation in apolipoprotein E knockout mice.

• DOI: 10.1002/jor.22216
• 发表时间: 2013-02
• 期刊: JOURNAL OF ORTHOPAEDIC RESEARCH
• 影响因子: 2.8
• 作者: Zhang, Dawei;Jin, Li;Reames, Davis L.;Shen, Francis H.;Shimer, Adam L.;Li, Xudong
• 通讯作者: Li, Xudong

The effects of simulated microgravity on intervertebral disc degeneration.

• DOI: 10.1016/j.spinee.2012.01.022
• 发表时间: 2013-03
• 期刊: The spine journal : official journal of the North American Spine Society
• 作者: Jin L;Feng G;Reames DL;Shimer AL;Shen FH;Li X
• 通讯作者: Li X

Link protein N-terminal peptide and fullerol promote matrix production and decrease degradation enzymes in rabbit annulus cells.

连接蛋白 N 端肽和富勒醇可促进兔环状细胞中的基质生成并减少降解酶。

• DOI: 10.1080/03008207.2017.1330333
• 发表时间: 2018
• 期刊: Connective tissue research
• 影响因子: 2.9
• 作者: Yeh,Ching-Hua;Chen,Dennis;Aghdasi,Bayan;Xiao,Li;Ding,Mengmeng;Jin,Li;Li,Xudong
• 通讯作者: Li,Xudong

Therapeutic effects of adenovirus-mediated growth and differentiation factor-5 in a mice disc degeneration model induced by annulus needle puncture.

• DOI: 10.1016/j.spinee.2009.10.006
• 发表时间: 2010-01
• 期刊: SPINE JOURNAL
• 影响因子: 4.5
• 作者: Liang, Haixiang;Ma, Shen-Ying;Feng, Gang;Shen, Francis H.;Li, Xudong Joshua
• 通讯作者: Li, Xudong Joshua

Intervertebral disk-like biphasic scaffold-demineralized bone matrix cylinder and poly(polycaprolactone triol malate)-for interbody spine fusion.

• DOI: 10.1177/2041731412454420
• 发表时间: 2012
• 期刊: Journal of tissue engineering
• 影响因子: 8.2
• 作者: Jin L;Wan Y;Shimer AL;Shen FH;Li XJ
• 通讯作者: Li XJ