Triplet Repeat Instability in Human Tissue Culture Cells

描述（由申请人提供）：三核苷酸重复序列（TNR）扩增导致至少15种神经退行性疾病，包括亨廷顿病（HD）、弗里德赖希共济失调、肌强直性营养不良和bbb90 %的遗传性脊髓小脑共济失调（SCAs）。虽然这些疾病是毁灭性的和无情的致命的，但它们显示出几个迷人的遗传特性。首先，这些突变发生的频率比自发突变高得多，在某些极端情况下，频率接近100%。此外，TNR扩增是一种独特的突变形式，其中重复的核苷酸三联体在连续几代之间线性扩增。重复序列的扩增也产生遗传预期，使TNR疾病的疾病表型恶化。我将使用罗伯特·拉休博士实验室最近优化的一种灵敏、特异、便携的遗传分析方法来研究人类细胞中TNR不稳定的病因。这项工作不仅使我能够在基础科学研究的一个有趣而重要的领域接受专家培训，而且还将使我能够推进我们对一整类致命神经系统疾病的理解。

DESCRIPTION (provided by applicant): Trinucleotide repeat (TNR) expansions cause at least 15 neurodegenerative disorders, including Huntington's disease (HD), Friedreich ataxia, myotonic dystrophy and >90% of inherited spinocerebellar ataxias (SCAs). While these diseases are devastating and relentlessly fatal, they show several fascinating genetic properties. First, these mutations occur at a much higher frequency that spontaneous mutations, in some extreme cases with a frequency approaching 100%. Also, TNR expansions are a unique form of mutation in which repeating triplets of nucleotides linearly amplify themselves between successive generations. Amplification of the repeating sequence also produces genetic anticipation, a worsening of disease phenotype of the TNR diseases. I will use a sensitive, specific and portable genetic assay recently optimized in the laboratory of Dr. Robert Lahue to investigate the etiology of TNR instability in human cells. This work will not only enable me to receive expert training in an interesting and important area of basic science research, but will also allow me to advance our understanding of an entire class of fatal neurological diseases.