Formation of the intervertebral disk: a molecular approach

描述（由申请人提供）：椎间盘位于每个椎体之间，对于维持脊柱的完整性至关重要。椎间盘的恶化，无论是由于物理损伤还是由于衰老，被认为是导致大多数背痛的原因。仅在美国，每年就有5000亿美元用于治疗背痛，目前还没有治愈受损/退化的椎间盘的方法。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。髓核脱水或损伤可导致椎间盘间负荷转移效率低下，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，当脊柱受压时，纤维环被认为有助于约束髓核。尽管椎间盘在日常生活中起着至关重要的作用，而且这种结构的损害给我们的医疗保健系统带来了巨大的经济负担，但人们对这种结构是如何形成的，也不知道这种组织中的分子是如何表达的。在这个建议中，我们描述了将揭示脊索转化为髓核的机制的实验（目的1）；确定髓核中的两种细胞类型是如何形成的（目的2）；研究体在椎间盘形成中的作用（目的3），并利用先前构建的小鼠突变体确定负责椎间盘形成的分子途径（目的1和4）。这些实验将更好地了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将来能够培养细胞用于（干细胞）治疗方案。

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.