DNA MICROSATELLITE REPEAT INSTABILITY AT THE FRIEDREICH AXTAXIA LOCUS

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。这笔赠款支持2006年春季学期25%的发布时间，让PI开展研究开发，以支持合作项目：基于模型的Friedreich共济失调基因微卫星重复序列不稳定性调查。Friedreich共济失调是最常见的遗传性共济失调，其临床特征为进行性共济失调、心肌病和糖尿病。它是由一种不寻常的DNA突变引起的，即FXN中GAA三联体重复(GAA-TR)序列的扩张。扩大的等位基因的长度决定了临床表现的严重程度。我们的目标是了解是什么使GAA-TR不稳定，并在患者的体细胞中逆转它，作为一种潜在的治疗策略。使用一种新的技术，允许检测单个细胞中的重复长度，我们最近发现GAA-TR序列表现出体细胞不稳定性，具有显著程度的细胞间和组织特异性变异，我们假设这种不稳定性是由错误的DNA复制和/或修复引起的。在这里，我们建议通过对从几个人类受试者尸检中分离出来的不同组织的GAA-TR长度变化数据进行数学建模，来检查这种不稳定是由复制或修复造成的。此外，对最佳拟合模型的最大似然参数估计的敏感性的检查将更具体地指出指导重复长度变异的复制和/或修复机制的特征，例如，各种GAA-TR等位基因的大突变和小突变(扩展/收缩)。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The grant supports 25% release time for spring semester 2006 for the PI to carry out research development in support of the collaborative project: A Model based investigation of DNA microsatellite repeat instability at the Friedreich ataxia locus. Friedreich ataxia, the most common inherited ataxia, is characterized clinically by progressive ataxia, cardiomyopathy and diabetes. It is caused by an unusual DNA mutation, the expansion of a GAA triplet-repeat (GAA-TR) sequence in the FXN. The length of the expanded allele determines the severity of the clinical presentation. Our goal is to understand what makes the GAA-TR unstable and to reverse it in somatic cells from patients as a potential therapeutic strategy. Using a novel technique that allows the detection of repeat lengths in individual cells, we recently discovered that the GAA-TR sequence displays somatic instability with a remarkable degree of cell-to-cell and tissue-specific variability, and we hypothesized that this instability is induced via erroneous DNA replication and/or repair. Here we propose to examine the likelihood that the instability results from replication or from repair by mathematically modeling the GAA-TR length variation data for various tissues isolated from several human subject autopsies. In addition, examination of the sensitivity of maximum likelihood parameter estimates for best-fitting models will more specifically indicate the features of replication and/or repair mechanisms that direct the repeat-length variation, e.g. large versus small mutations (expansions / contractions) of the various GAA-TR alleles.