A Wnt/Shh signaling loop controls intervertebral disc growth and differentiation

Wnt/Shh 信号环路控制椎间盘生长和分化

• 批准号: 8759103
• 负责人: Chitra L Dahia
• 金额: $ 38.72万
• 依托单位: HOSPITAL FOR SPECIAL SURGERY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8759103
• 关键词: Affect; Age; Aging; Agonist; Biological; Biological Assay; Biological Response Modifier Therapy; Birth; Blood Circulation; Cell Differentiation process; Cell Nucleus; Cell Proliferation; Cells; Data; Development; Differentiation Antigens; Differentiation and Growth; Down-Regulation; Epiphysial cartilage; Feedback; Fibrosis; Future; Gait; Gene Targeting; Goals; Growth; Histology; In Vitro; Indium; Injury; Intervertebral disc structure; Joints; Knowledge; Lead; Ligands; Liquid substance; Low Back Pain; Magnetic Resonance Imaging; Medical; Modeling; Molecular; Movement; Mus; Muscle; Nature; Neurologic; Operative Surgical Procedures; Pathway interactions; Proteoglycan; Quality of life; Role; SHH gene; Signal Pathway; Signal Transduction; Site; Symptoms; Testing; Time; Treatment Cost; Up-Regulation; age related; base; disc regeneration; fetal bovine serum; in vivo; inhibitor/antagonist; insight; intervertebral disk degeneration; molecular marker; novel; nucleus pulposus; palliative; postnatal; premature; public health relevance; receptor; research study; spine bone structure; vertebra body

DESCRIPTION (provided by applicant): This project aims to identify the molecular mechanisms of postnatal growth and differentiation of the intervertebral disc (IVD), and how these mechanisms are down-regulated, leading to age-related changes in the IVD. Each IVD consists of a central semi-liquid nucleus pulposus (NP), surrounded by a multi-layered annulus fibrosus (AF), and connected to the bodies of the adjacent vertebral bodies by cartilagenous end plates (EP). Together, these components form a strong joint that resists both tension and compression forces between vertebrae. Degenerative disc disease (DDD) is a major cause of lower back pain, and other neurological symptoms leading to a decreased quality of life. DDD is extremely common, affecting as many as one in seven people. The treatment costs are high, and often include surgical intervention. However, treatment is essentially palliative, since it treats the effects of disc degeneration rather than the causes. The long-term goal of this project is to identify potential biological approaches to therapy, using the same pathways by which the IVD normally grows and differentiates. We have developed the mouse lumbar IVD as a model, and preliminary data shows that it can be used to identify the signaling pathways in the IVD that control postnatal growth and differentiation. We have found that during postnatal growth, the NP acts as a signaling center that controls both growth and differentiation. NP cells express SHH, and blockade of Shh signaling both in vitro and in vivo shows that it is essential for cell proliferation and differentiation of the IVD. NP cells also express several Wnt ligands, which are required to maintain Shh signaling in the IVD. Both these signaling pathways, and the downstream targets of Shh signaling, are down-regulated by the end of the growth period. However, Shh signaling, and the expression of differentiation markers, can be re-activated after the growth period by signals present in fetal bovine serum, or by Wnt agonists, showing that down-regulation of growth and differentiation is not irreversible, and offers potential future targets for therapy. Aim 1 of the project tests the hypothesis that the duration of the postnatal growth period is determined by active Wnt signaling. Aim 2 tests the hypothesis that a feedback loop between Wnt and Shh signaling is established by Wnt inhibitors expressed downstream of Shh signaling. Aim 3 tests the hypothesis that circulating signals control the synchronous growth of all the IVDs by acting on Wnt/Shh signaling loop in the NP. The data from this project will provide the necessary information to explore further the nature of aging of the IVD, the basis of possible biological therapies for disc injury or degeneration, and novel scientific insights into te way growth and differentiation of the IVDs are controlled during postnatal growth.

描述（由申请人提供）：该项目旨在确定椎间盘（IVD）出生后生长和分化的分子机制，以及这些机制如何下调，导致IVD的年龄相关变化。每个IVD由中央半液体髓核（NP）组成，被多层纤维环（AF）包围，并通过软骨终板（EP）连接到相邻椎体的主体。这些组件一起形成了一个坚固的关节，可以抵抗椎骨之间的张力和压缩力。退行性椎间盘疾病（DDD）是下背痛和其他神经系统症状的主要原因，导致生活质量下降。DDD非常常见，影响多达七分之一的人。治疗费用很高，通常包括手术干预。然而，治疗本质上是姑息性的，因为它治疗的是椎间盘退变的影响，而不是原因。该项目的长期目标是确定潜在的生物治疗方法，使用与IVD正常生长和分化相同的途径。我们已经开发了小鼠腰椎IVD作为模型，初步数据表明，它可以用于识别IVD中控制出生后生长和分化的信号通路。我们已经发现，在出生后的生长，NP作为一个信号中心，控制生长和分化。NP细胞表达SHH，体外和体内Shh信号传导的阻断表明其对于IVD的细胞增殖和分化是必需的。NP细胞还表达几种Wnt配体，其是维持IVD中Shh信号传导所需的。这两种信号通路，以及Shh信号的下游靶点，在生长期结束时下调。然而，Shh信号传导和分化标志物的表达可以在生长期后通过胎牛血清中存在的信号或通过Wnt激动剂重新激活，表明生长和分化的下调不是不可逆的，并且提供了潜在的未来治疗靶点。该项目的目标1测试了出生后生长期的持续时间由活跃的Wnt信号决定的假设。目的2测试Wnt和Shh信号传导之间的反馈回路由Shh信号传导下游表达的Wnt抑制剂建立的假设。目的3验证循环信号通过作用于NP中的Wnt/Shh信号环来控制所有IVD的同步生长的假设。该项目的数据将提供必要的信息，以进一步探索IVD老化的性质，椎间盘损伤或退变的可能生物疗法的基础，以及对出生后生长期间IVD生长和分化控制方式的新科学见解。