Modulation of Translation Termination Fidelity

我的研究生涯的主题一直是通过各种方法了解控制不同系统中基因表达调控的机制。利用分子生物学技术，研究了研究生院EB病毒裂解感染过程中晚期基因表达的调控。通过生物化学方法，我最近一直在研究一种新的纯蛋白质(Prion)机制，用于调节酵母中的翻译终止保真度。哺乳动物的严重神经退行性疾病(如亨廷顿氏症、阿尔茨海默氏症和传染性海绵状脑病)的发展被认为是通过相关的过程发生的。有了这个奖项，我将把我的博士后培训扩展到遗传和细胞生物学技术，将我的体外研究扩展到体内系统。我的目标是阐明真核细胞释放因子3作为普鲁恩可逆灭活的分子机制以及这一过程的调节。我打算在一家学术机构建立一个独立的研究项目，通过多学科的方法，对翻译终止过程、其规则以及翻译歧义的后果产生机械性的理解。准确的终止对于忠实的蛋白质合成是必不可少的，这个系统中的错误已经与近200种遗传疾病联系在一起。我的研究将集中在：1)确定在终止过程中活跃的因素和调节谨慎步骤的信号，以及2)识别和表征新的和现有的终止效率修饰物的功能和目标。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础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.