mRNA decay mechanisms for ER stress recovery

这个项目的目的是建立在我作为博士后学者所做工作的基础上，跟踪令人兴奋的线索 由于发现了一种细胞用来从压力中恢复并扩展这些细胞的新机制， 作为一名独立调查员，我将研究新的领域。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将使我能够学习新技术并扩大我的 研究，并在较长期内开发我自己的研究计划，重点是mRNA调控和它的 与本地化和应激恢复的关系。 作为加州大学旧金山分校乔纳森·韦斯曼实验室的博士后，我初步描述了一种新的途径 作为应对折叠应激的一种方式，细胞通过降解定位于内质网的mRNAs 在这个隔间里。这条途径有许多生理和机械方面的方面， 并可能提供对细胞如何在急性应激中生存下来的洞察，一种特定的内切酶是如何 参与了广泛的mRNAs的衰变，以及定位如何影响mRNAs的稳定性和 监管。本申请中描述的研究旨在直接解决这些问题中的每一个， 采用基因组和小规模实验相结合的方法。 本文概述的研究将进一步加深我们对细胞如何生存和适应压力的理解。 呃，一种与多种人类疾病有关的疾病，包括糖尿病和阿尔茨海默氏症 疾病，以及病毒感染。了解细胞如何应对这种情况将直接相关 有助于我们了解这些疾病的发病机制。例如，肥胖症与 而2型糖尿病被认为是由内质网应激，特别是IRE1，一种其 在这项研究中，功能将被直接研究。

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.