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）（IVD）的产后生长和分化的分子机制，以及如何下调这些机制，从而导致IVD年龄相关的变化。每个IVD由中央半液体核（NP）组成，周围环绕多层纤维纤维（AF），并通过软骨端端平板（EP）连接到相邻椎体的身体。这些组件共同形成了一个强的关节，该关节既抵消椎骨之间的张力和压缩力。退化性椎间盘疾病（DDD）是下背痛的主要原因，其他神经系统症状导致生活质量降低。 DDD非常普遍，影响了多达七分之一的人。治疗成本很高，通常包括手术干预。但是，治疗本质上是姑息治疗的，因为它可以治疗椎间盘变性的作用而不是原因。该项目的长期目标是使用IVD通常增长和区分的相同途径来确定潜在的治疗生物学方法。我们已经开发了小鼠腰椎IVD作为模型，初步数据表明，它可用于识别IVD中控制产后生长和分化的IVD信号传导途径。我们发现，在产后生长期间，NP充当控制生长和分化的信号传导中心。 NP细胞在体外和体内表达SHH，SHH信号的阻塞表明，它对于IVD的细胞增殖和分化至关重要。 NP细胞还表达了几种Wnt配体，这些配体需要在IVD中维持SHH信号。这些信号通路和SHH信号的下游目标在生长期结束时都下调。但是，SHH信号传导和分化标记的表达可以在生长期后通过胎牛血清中存在的信号或Wnt激动剂来重新激活，表明生长和分化的下调不是不可逆转的，并提供了潜在的未来治疗靶标。该项目的目标1检验了以下假设：产后生长周期的持续时间是由主动Wnt信号确定的。 AIM 2检验了以下假设：Wnt抑制剂在SHH信号下游表达的Wnt抑制剂建立了Wnt和SHH信号之间的反馈回路。 AIM 3检验了以下假设：循环信号通过作用于NP中的Wnt/SHH信号环，控制所有IVD的同步生长。该项目的数据将提供必要的信息，以进一步探索IVD衰老的性质，椎间盘损伤或变性的可能生物学疗法的基础，以及在产后生长过程中控制IVD的生长和分化的新科学见解。