The genetic basis of disc disease

椎间盘疾病的遗传基础

• 批准号: 8444994
• 负责人: BRIAN David HARFE
• 金额: $ 19万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8444994
• 关键词: Affect; Age; Alleles; American; Animals; Back Pain; Bioinformatics; Biological Assay; Biological Models; Chromosomes; Data; Defect; Deterioration; Development; Disabled Persons; Disease; Ethylnitrosourea; Gene Expression; Genes; Genetic; Genetic Screening; Goals; Healed; Healthcare Systems; Human; Individual; Intervertebral disc structure; Knowledge; Laboratories; Lesion; Life; Maintenance; Medical; Molecular; Molecular Target; Morphology; Mouse Strains; Mus; Mutation; Nuclear Localization Signal; Pathway interactions; Patients; Pattern; Play; Process; Proteins; Reporter; Research; Risk; Role; Structure; Symptoms; Techniques; Therapeutic; Time; Tissues; Use of New Techniques; Vertebral column; Vertebrates; age related; base; cost; design; exome; gene therapy; genome wide association study; genome-wide; healing; innovation; intervertebral disk degeneration; mouse model; mutant; next generation sequencing; novel; novel strategies; nucleus pulposus; postnatal; public health relevance; repaired; screening; spine bone structure

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.

描述（由申请人提供）：位于椎骨之间的椎间盘退化在老年脊椎动物中很常见。腰椎间盘相关的变化被认为是导致大多数背痛的原因。仅在美国，每年就有超过500亿美元用于治疗背痛，并且目前还没有治疗受损和/或退化的椎间盘的方法。治疗椎间盘疾病引起的背痛将是数百万美国人改变生活的重大医学进步。尽管椎间盘在日常生活中发挥着重要作用，并且这些结构的巨大经济负担给我们的医疗保健系统带来了损害。 关于在该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，无偏见的遗传筛选，以确定负责形成椎间盘的基因。许多成功的全基因组遗传筛选先前已在小鼠中进行。这些筛选都不是为了发现影响椎间盘的突变，识别椎间盘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，我们建议在椎间盘表达eYFP并因此发光的小鼠品系中进行筛选。这将使我的研究团队能够快速确定椎间盘是否已经丢失（由于缺乏eYFP）或失去其结构完整性（eYFP以异常模式存在）。如果不使用这个 新的策略，这将是非常困难的，以确定影响光盘的突变。由于基因筛选将在出生后的小鼠中进行，我的实验室将能够识别基因，一旦突变，是可行的，并影响维持或形成的光盘。缺乏分子靶点来开发基于蛋白质或基因的疗法来停止或治愈已受损或正在退化的椎间盘，这极大地限制了数百万患有这些疾病的患者的治疗选择。提出的创新屏幕是有风险的，但有可能产生更多的知识分子组成部分参与形成和维持光盘结构比整个领域已经产生在过去50年。