The Biological Function of Bacterial Argonaute Proteins

描述(申请人提供)：已证明在真核生物转录后基因沉默中，ArgAerte蛋白发挥关键作用；然而，它们在细菌中的生物学功能几乎仍未确定。这项工作的广泛目标是了解ArgAerte蛋白对细菌基因表达的调节影响。我将以嗜热嗜热杆菌为模型原核生物，利用分子遗传学方法对细菌ArgAerte蛋白相关的核酸进行鉴定，研究ArgAerte对细菌mRNAs的调控作用，并鉴定参与ArgAerte介导的细菌基因沉默的其他蛋白质。这些研究应该为细菌蛋白的生物学功能提供重要的见解，细菌蛋白在理解真核生物中同源Argavite蛋白的结构和酶活性方面发挥了关键作用。 与公共卫生的相关性：众所周知，microRNAs、siRNAs和它们所关联的ArgAerte蛋白对细胞功能做出了关键贡献。MicroRNAs与许多疾病有关，包括癌症、微生物感染、心血管疾病、肾脏疾病等。此外，siRNAs是一种潜在的治疗人类疾病的药物。通过研究细菌Argavies的生物学功能，我们将深入了解一种尚未被了解的原核生物基因调控的新机制。此外，细菌蛋白作为理解其哺乳动物同源物功能的范例的良好价值使我们相信，拟议的研究将为真核细胞ArgAerte蛋白的功能提供重要的新见解。)

DESCRIPTION (provided by applicant): Argonaute proteins have been shown to play a critical role in post-transcriptional gene silencing in eukaryotes; however, their biological function in bacteria remains almost entirely uncharacterized. The broad objectives of this work are to understand the regulatory influence of Argonaute proteins on bacterial gene expression. Using Thermus thermophilus as a model prokaryotic organism, I will employ molecular genetics methods to characterize the nucleic acids associated with a bacterial Argonaute protein, to examine the regulatory effects of Argonaute on bacterial mRNAs, and to identify additional proteins involved in Argonaute-mediated gene silencing in bacteria. These studies should provide important insights into the biological function of a bacterial protein that has played a pivotal role as a paradigm for understanding the structure and enzymatic activity of homologous Argonaute proteins in eukaryotes. PUBLIC HEALTH RELEVANCE: It is well appreciated that microRNAs, siRNAs and the Argonaute proteins with which they associate make critical contributions to cellular function. MicroRNAs have been implicated in many diseases, including cancer, microbial infection, cardiovascular disease, kidney disease, etc. Moreover, siRNAs are potential therapeutic agents for combating human disease. By studying the biological function of bacterial Argonautes, we will gain insight into a novel mechanism of prokaryotic gene regulation that is not yet understood. Furthermore, the well established value of bacterial proteins as paradigms for understanding the function of their mammalian homologues makes us confident that the proposed studies will provide important new insights into the function of eukaryotic Argonaute proteins. )