Formation of the Intervertebral Disk: a Molecular Approach

描述（由申请人提供）：椎间盘位于各椎骨之间，对于维持脊柱的完整性至关重要。椎间盘的退化，无论是通过物理损伤或通过老化，被认为是导致大多数情况下的背痛。仅在美国，每年就有超过500亿美元花费在背痛的治疗上，并且目前还没有针对受损/退化的椎间盘的治愈方法。椎间盘的中心区域由称为髓核的柔软、高度水合的组织组成。脱水或髓核损伤会导致椎间盘之间的负荷转移效率低下，导致椎间盘突出和其他类型的椎间盘疾病。髓核被纤维环包围，当压力施加到脊柱时，纤维环被认为有助于限制髓核。尽管椎间盘在日常生活中发挥着重要作用，并且这种结构给我们的医疗保健系统带来了巨大的经济负担，但人们对这种结构如何形成以及这种组织中表达的分子知之甚少。在这个建议中，我们描述了一些实验，这些实验将揭示脊索转化为髓核的机制（目标1）;确定髓核中的两种细胞类型是如何形成的（目标2）;体节在椎间盘形成中的作用（目标3），并使用先前构建的小鼠突变体鉴定负责盘形成的分子途径（目的1和4）。这些实验将更好地理解椎间盘形成所需的分子和细胞机制，并确定负责形成这一重要结构的祖细胞。椎间盘祖细胞群的鉴定将使我们能够在未来培养细胞用于（干）细胞为基础的治疗方案。 公共卫生相关性：椎间盘在脊柱运动中起着至关重要的作用，该组织的损伤导致大多数报告的背痛病例。正常的椎间盘由三个不同的区域组成：称为纤维环的纤维软骨的厚的外环;被称为髓核的纤维环包围的凝胶状材料;以及上级和下部软骨终板。本提案的目标是确定髓核形成的细胞和分子机制，并揭示在该结构中发现的两种细胞类型，软骨细胞样细胞和脊索细胞是如何衍生的。

DESCRIPTION (provided by applicant): The intervertebral disks are located between each vertebra and are essential for maintaining the integrity of the spinal column. Deterioration of the intervertebral disks, either by physical damage or through aging, is thought to cause most cases of back pain. In the US alone >50 billion dollars a year are spent on the treatment of back pain and there are presently no cures for a damaged/degenerating intervertebral disk. The center region of the intervertebral disk is composed of a soft, highly hydrated tissue called the nucleus pulposus. Dehydration or damage to the nucleus pulposus can result in inefficient transfer of load between the intervertebral disks, leading to disk herniation and other types of disk disease. The nucleus pulposus is surrounded by the annulus fibrosus, which is thought to help constrain the nucleus pulposus when pressure is applied to the spine. In spite of the essential role the intervertebral disks play in everyday life and the huge financial burden damage to this structure places on our health care system there is very-little known about how this structure forms nor the molecules expressed in this tissue. In this proposal we describe experiments that will uncover the mechanism responsible for transforming the notochord into the nucleus pulposus (Aim 1); determine how the two cell types in the nucleus pulposus are formed (Aim 2); what the role of the somites is in the formation of the intervertebral disks (Aim 3), and identify the molecular pathways responsible for disk formation using previously constructed mouse mutants (Aims 1 and 4) . These experiments will yield a better understanding of the molecular and cellular mechanisms required for formation of the intervertebral disks and identify the progenitor cells responsible for forming this important structure. The identification of the intervertebral disk progenitor populations will allow us in the future to culture cells for use in (stem) cell-based treatment protocols. Public Health Relevance: The intervertebral disks play an essential role in how the spine moves and damage to this tissue causes the majority of the reported cases of back pain. The normal intervertebral disk is composed of three distinct regions: a thick outer ring of fibrous cartilage called the annulus fibrosus; a gel-like material that is surrounded by the annulus fibrosus called the nucleus pulposus; and superior and inferior cartilaginous end plates. The goals of this proposal are to determine the cellular and molecular mechanism(s) responsible for the formation of the nucleus pulposus and to uncover how the two cell types found in this structure, chondrocyte-like and notochordal cells, are derived.