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Advances in the in vitro study of Huntington's disease mutagenesis and pathogenesis.

机译：亨廷顿舞蹈病的诱变和发病机制的体外研究进展。

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摘要

Huntington's disease (HD) is a devastating neurodegenerative disorder caused by the expansion of a CAG·CTG tract within exon 1 of the gene for the huntingtin protein. The mechanisms by which such expansions occur and how they lead to eventual neurodegeneration are poorly understood. This dissertation applies existing model systems, describes the creation of a new model system, and lays a foundation for the development of newer models to address the important mechanistic questions about HD mutagenesis and pathogenesis. I determined that two homologs of DNA repair proteins identified as modulators of trinucleotide repeat (TNR) mutagenesis in yeast screens do not contribute to TNR stability in cultured human cells. I did find, however, that several important cis-acting mechanistic features of HD genetics are recapitulated in a new selective system for detecting TNR expansions in cultured astrocytes, including length-dependence, the ability to form aberrant DNA secondary structures, TNR tract purity, and DNA replication. I also determined that the specific ROCK (Rho-associated coiled coil kinase) inhibitor Y-27632 enhances important single-cell culture techniques needed to make scientific and therapeutic use of human pluripotent stem cells as HD model systems or therapies. This process also led to several mechanistic insights into the function of ROCK inhibitors. Finally, I examined the transcriptional regulation of an important transcription regulator and oncogene implicated in HD pathogenesis, Bmi1. In so doing, I identified important cis-regulatory features of two Bmi1 promoters that may be exploitable for HD therapy or studying HD pathogenesis. Together these significant findings lay the foundation for further study of the mechanisms of mutation and pathology in HD using in vitro model systems.
机译：亨廷顿舞蹈病（HD）是一种毁灭性神经退行性疾病，由亨廷顿蛋白基因第1外显子中的CAG·CTG束扩张引起。人们对这种扩张发生的机制及其如何导致最终的神经退行性了解甚少。本文运用现有的模型系统，描述了新模型系统的创建，并为开发新模型奠定了基础，以解决有关高清诱变和发病机理的重要机理问题。我确定在酵母筛选中被鉴定为三核苷酸重复（TNR）诱变调节剂的DNA修复蛋白的两个同源物对培养的人细胞中的TNR稳定性没有贡献。但是，我确实发现，HD遗传学的几个重要的顺式作用机理特征在一个新的选择性系统中得到了概括，该系统可以检测培养的星形胶质细胞中的TNR扩展，包括长度依赖性，形成异常DNA二级结构的能力，TNR道纯度，和DNA复制。我还确定了特定的ROCK（Rho相关的卷曲螺旋激酶）抑制剂Y-27632增强了将人类多能干细胞作为HD模型系统或疗法进行科学和治疗用途所需的重要单细胞培养技术。该过程还导致了对ROCK抑制剂功能的一些机械学见解。最后，我检查了一种重要的转录调节因子和致癌基因Bmi1参与的高清转录调控。通过这样做，我确定了两个Bmi1启动子的重要顺式调节功能，这些启动子可用于HD治疗或研究HD发病机理。这些重要发现共同为使用体外模型系统进一步研究HD突变和病理机制奠定了基础。

著录项

  • 作者

    Claassen, David Alan.;

  • 作者单位

    University of Nebraska Medical Center.;

  • 授予单位 University of Nebraska Medical Center.;
  • 学科 Biology Molecular.;Biology Genetics.;Biology Neuroscience.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 159 p.
  • 总页数 159
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

  • 入库时间 2022-08-17 11:38:01

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