Age-related changes in the intervertebral disk.

描述(申请人提供)：位于每个椎骨之间的间盘退化在老年脊椎动物中很常见。与年龄相关的椎间盘变化被认为是导致大多数背部疼痛的原因。背部疼痛几乎影响到每个人生命中的某个时刻，每年有150万人成为残疾人。椎间盘的中心区域由称为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。没有治愈磁盘损坏/退化的方法。Hedgehog和BMP信号通路都参与了许多组织的形成和出生后的维持，但目前还没有必要的工具来研究这些重要的信号通路在椎间盘中的功能。在这项提案中，我们将使用新的小鼠染色和我们最近开发的技术来验证我们的假设，即刺猬和BMP信号通路的变化是年龄相关的椎间盘退变的原因。在目标1中，我们将研究Hedgehog信号在椎间盘发育和维持中的作用。目的2将研究特定的刺猬家族成员Shh在健康腰椎间盘的胚胎后维持中所起的作用。在目标3中，我们建议从椎间盘中移除BMP蛋白的组合，BMP蛋白在Hedgehog信号的下游发挥作用，以验证我们的假设，即BMP蛋白对椎间盘细胞的刺激不足会导致椎间盘退变。

DESCRIPTION (provided by applicant): Deterioration of the intervertebral disks, located between each vertebra, is common in older vertebrates. Age-related changes in the intervertebral disks are thought to cause most cases of back pain. Back pain affects nearly everyone at some point of their lives, with 1.5 million people a year becoming disabled. The center region of the intervertebral disk is composed of 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. There are no cures for disk damage/degeneration. Both the hedgehog and Bmp signaling pathways have been implicated in the formation and postnatal maintenance of a number of tissues, however the tools necessary to investigate the function of these important signaling pathways in the intervertebral disks have not been available. In this proposal, we will use novel mouse stains and techniques we have recently developed to test our hypothesis that alterations in hedgehog and Bmp signaling pathways are responsible for age-related disk degeneration. In Aim 1, the role of hedgehog signaling in the development and maintenance of the intervertebral disks will be examined. Aim 2 will investigate the role a specific hedgehog family member, Shh, plays in the postembryonic maintenance of healthy intervertebral disks. In Aim 3, we propose to remove combinations of Bmp proteins, which function downstream of hedgehog signaling, from the intervertebral disks to investigate our hypothesis that inadequate stimulation of intervertebral disk cells by Bmp proteins results in disk degeneration.