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。我的目标是利用加州大学旧金山分校的大量资源和专业知识，使我能够学习新技术，扩大我的研究，并在长期内发展我自己的研究计划，重点是mRNA调控及其与压力定位和恢复的关系。 作为加州大学旧金山分校Jonathan Weissman实验室的博士后，我最初描述了一种新的途径，通过这种途径，细胞降解定位于内质网的mRNA，作为应对内质网折叠应激的一种方式。该途径有许多生理和机制方面尚未探索，可能有助于了解细胞如何在急性应激中存活，特定的核酸内切酶如何参与广谱mRNA的衰变，以及定位如何影响mRNA的稳定性和调节。本申请中描述的研究旨在直接解决这些问题中的每一个，使用基因组和小规模实验的组合。 这里概述的研究将进一步了解细胞如何在ER中生存和适应压力，这种情况与多种人类疾病有关，包括糖尿病和阿尔茨海默病以及病毒感染。了解细胞如何科普这种情况将直接关系到我们对这些疾病的机制的理解。例如，肥胖和2型糖尿病之间的关系已被提出是由ER应激介导的，特别是Ire 1，该蛋白质的功能将在本研究中直接研究。

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.