The genetic basis of disc disease

描述(申请人提供)：位于椎骨之间的间盘退化在较年长的脊椎动物中很常见。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。仅在美国，每年就有500亿美元用于治疗背部疼痛，目前还没有治愈受损和/或退变的椎间盘的方法。对于数百万美国人来说，治疗腰椎间盘疾病引起的背痛将是一项重大的医疗进步，改变了他们的生活。尽管椎间盘在日常生活中发挥着至关重要的作用，而且对这些结构造成了巨大的财政负担，但对我们的卫生保健系统造成了损害。人们对作用于该组织的分子途径知之甚少。我们建议在小鼠身上进行一种创新的全基因组、无偏见的遗传筛查，以确定负责形成椎间盘的基因。此前已经在小鼠身上进行了许多成功的全基因组基因筛查。这些筛查的设计都不是为了揭示影响椎间盘的突变，而识别这些突变需要对脊柱进行广泛的处理。为了克服这一劳动密集型障碍，我们建议在一种品系的小鼠身上进行筛查，在这种品系中，椎间盘表达EYFP，因此会发光。这将使我的研究团队能够快速确定光盘是否已丢失(由于缺少EYFP)或已失去其结构完整性(EYFP以异常模式出现)。如果不使用这个 新的策略要确定影响视盘的突变将是极其困难的。由于TE筛查将在出生后的小鼠身上进行，我的实验室将能够识别出突变后具有活性并影响椎间盘维持或形成的基因。由于缺乏分子靶点来开发基于蛋白质或基因的疗法来阻止或治愈已损坏或正在退化的椎间盘，极大地限制了数百万患有这些疾病的患者的治疗选择。拟议的创新筛选是有风险的，但有可能产生比整个领域在过去50年中产生的更多关于形成和维持盘状结构所涉及的分子成分的知识。

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.