The genetic basis of disc disease

描述（由申请人提供）：位于椎体之间的椎间盘恶化在老年脊椎动物中很常见。年龄相关的椎间盘变化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和/或退化的椎间盘的方法。如果能治愈腰椎间盘疾病引起的背痛，对数百万美国人来说将是一项改变生活的重大医学进步。尽管椎间盘在日常生活中起着至关重要的作用，但对这些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。我们对这种组织中起作用的分子途径知之甚少。我们建议在小鼠中进行创新的全基因组，无偏倚的遗传筛选，以确定负责形成椎间盘的基因。许多成功的全基因组基因筛选已经在老鼠身上进行过。这些筛选都不是为了发现影响椎间盘的突变而设计的，因为确定这些突变需要对脊柱进行大量的处理。为了克服这一劳动密集型障碍，我们建议在一种椎间盘表达eYFP并因此发光的小鼠中进行筛选。这将使我的研究小组能够快速确定椎间盘是否已经丢失（由于缺乏eYFP）或已经失去其结构完整性（eYFP以异常模式存在）。不用这个

DESCRIPTION (provided by applicant): Deterioration of the intervertebral discs, located between the vertebrae, is common in older vertebrates. Age-related changes in the intervertebral discs are thought to cause most cases of back pain. In the US alone, >50 billion dollars per year are spent on the treatment of back pain, and there is presently no cure for a damaged and/or degenerating intervertebral disc. A cure for back pain caused by disc disease would be a monumentally life-altering medical advance for millions of Americans. In spite of the essential role the intervertebral discs play in everyday life and the huge financial burden damage to these structures places on our health care system. There is very little known about the molecular pathways acting in this tissue. We propose to perform an innovative genome-wide, unbiased genetic screen in mice to identify genes that are responsible for forming the intervertebral disc. A number of successful genome-wide genetic screens have previously been performed in mice. None of these screens were designed to uncover mutations affecting the intervertebral discs, identification of which would have required extensive processing of the vertebral column. To overcome this labor-intensive hurdle, we propose to perform our screen in a strain of mice in which the intervertebral discs express eYFP, and therefore glow. This will allow my research team to quickly determine if discs have been lost (by absence of eYFP) or have lost their structural integrity (eYFP present in an abnormal pattern). Without the use of this novel strategy it would be extremely difficult to identify mutations that affect the discs. Since te screen will be performed in postnatal mice, my laboratory will be able to identify genes that, upon mutation, are viable and affect maintenance or formation of the discs. The lack of molecular targets for the development of protein- or gene-based therapies to halt or heal discs that have been damaged or are degenerating has greatly limited treatment options for millions of patients suffering from these conditions. The proposed innovative screen is risky but has the potential to generate more knowledge about the molecular components involved in forming and maintaining disc structure than the entire field has generated in the last 50 years.