Modulation of Translation Termination Fidelity

我的研究生涯的主题是通过各种方法来了解不同系统中基因表达调控的机制。利用分子生物学技术，我研究了晚期基因表达的调控在爱泼斯坦巴尔病毒裂解感染在研究生院。通过生物化学的方法，我最近一直在研究一种新的蛋白质（朊病毒）的机制，调节翻译终止保真度酵母。据信，哺乳动物中严重神经退行性疾病（例如，亨廷顿氏病、阿尔茨海默氏病和传染性海绵状脑病）的发展通过相关过程发生。有了这个奖项，我将扩大我的博士后培训，遗传和细胞生物学技术，通过扩展我的体外研究，在体内系统。我的目标是阐明真核细胞释放因子3作为朊病毒可逆失活的分子机制以及这一过程的调控。我打算在一个学术机构建立一个独立的研究项目，通过多学科的方法来发展对翻译终止过程，其调节以及翻译歧义的后果的机械理解。精确的终止对于蛋白质的忠实合成至关重要，该系统中的错误与近200种遗传疾病有关。我的教师研究将集中在：1）确定活跃的因素和信号调节终止的谨慎步骤，2）识别和表征终止效率的新的和现有的修饰符的功能和目标。只有通过对这一过程的全面了解，我们才能充分认识到它在基本细胞生理学和人类疾病中的作用。

The theme of my research career has been to understand mechanisms governing the regulation of gene expression in diverse systems through a variety of approaches. Using molecular biology techniques, I investigated the regulation of late gene expression during Epstein Barr virus lytic infection in graduate school. Through biochemical approaches, I have recently been investigating a novel protein-only (prion) mechanism for regulating translation termination fidelity in yeast. The development of severe neurodegenerative disorders in mammals (e.g. Huntington's, Alzheimer's, and the transmissible spongiform encephalopathies) is believed to occur through a related process. With this award, I will broaden my post-doctoral training to genetic and cell biological techniques by extending my in vitro studies to the in vivo system. My goal is to elucidate the molecular mechanism by which eukaroytic release factor 3 is reversibly inactivated as a prion and the regulation of this process. I intend to establish an independent research program at an academic institution to develop a mechanistic understanding of the translation termination process, its regulation, and the consequences of translational ambiguity through multidisciplinary approaches. Accurate termination is essential for faithful protein synthesis, and errors in this system have been linked to nearly 200 genetic disorders. My faculty research will focus on: 1)determining the factors active in and the signals regulating discreet steps in termination, and 2) identifying and characterizing the functions and targets of new and existing modifiers of termination efficiency. It is only through a complete understanding of this process that we can fully appreciate its role in basic cellular physiology and human disease.