Formation of the intervertebral disk: a molecular approach

描述(申请人提供)：间盘位于每个椎体之间，对于保持脊柱的完整性是必不可少的。腰间盘的恶化，无论是由于身体损伤还是由于衰老，被认为是导致大多数背部疼痛的原因。仅在美国，每年就有500亿美元花在背部疼痛的治疗上，目前还没有治疗受损/退变的椎间盘的方法。椎间盘的中心区域由一种叫做髓核的高度水化的软组织组成。脱水或髓核受损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，纤维环被认为在向脊柱施压时帮助约束髓核。尽管椎间盘在日常生活中扮演着重要的角色，而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，但人们对这种结构是如何形成的，以及这种组织中表达的分子知之甚少。在这项建议中，我们描述了一些实验，这些实验将揭示负责将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确定负责椎间盘形成的分子路径(目标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前体细胞。对椎间盘祖细胞群体的鉴定将使我们能够在未来培养细胞，用于(干细胞)治疗方案。 公共卫生相关性：椎间盘在脊柱的运动方式中起着至关重要的作用，而对这一组织的破坏会导致大多数已报道的背痛病例。正常的椎间盘由三个不同的区域组成：称为纤维环的厚厚的纤维软骨外环；被称为髓核的纤维环包围的凝胶状物质；以及上下软骨终板。这项提议的目的是确定负责髓核形成的细胞和分子机制(S)，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--是如何产生的。

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.