mRNA decay mechanisms for ER stress recovery

描述（由申请人提供）：该项目旨在建立在我作为博士后学者所做的工作基础上，遵循发现细胞用于从压力中恢复的新机制所开辟的令人兴奋的线索，并将这些研究扩展到我将作为独立研究者研究的新领域。我的目标是利用UCSF的大量资源和专业知识，这将使我能够学习新技术并扩展我的研究，从长远来看，我将开发自己的研究项目，专注于mRNA调节及其与定位和压力恢复的关系。

DESCRIPTION (provided by applicant): This project is designed to build upon work I have done as a postdoctoral scholar, to follow exciting leads opened up by the discovery of a new mechanism cells employ to recover from stress, and expand these studies into new areas that I will study as an independent investigator. My goals are draw upon the substantial resources and expertise at UCSF that will allow me to learn new techniques and expand my research, and in the longer term to develop my own research program focused on mRNA regulation and its relationship to localization and recovery from stress. As a postdoc in Jonathan Weissman's laboratory at UCSF, I have initially characterized a new pathway by which cells degrade mRNAs localized to the endoplasmic reticulum as a way of coping with folding stress in this compartment. There are many physiological and mechanistic aspects of this pathway that are unexplored and are likely to provide insight into how cells survive acute stress, how a specific endonuclease participates in the decay of a broad spectrum of mRNAs, and how localization affects mRNA stability and regulation. The research described in this application is designed to address each of these issues directly, using a combination of genomic and smaller scale experiments. The research outlined here will further our understanding of how cells survive and adapt to stress in the ER, a condition that has been linked to a variety of human diseases, including diabetes and Alzheimer's disease, as well as viral infection. Understanding how cells cope with this situation will have direct relevance to our understanding of the mechanisms of these diseases. For example, the relationship between obesity and type 2 diabetes has been proposed to be mediated by ER stress and in particular Ire1, a protein whose function will be directly investigated in this study.