Translational control of stress response signaling

项目摘要 细胞的应激反应机制是细胞适应各种环境和 生理条件。该研究项目的总体目标是了解细胞是如何调节信使核糖核酸的 翻译是他们适应压力过程的一部分。特别有趣的是一条被称为 整合应激反应(ISR)，由应激激活的eIF2a激酶启动，它对几个 不同类型的压力。ISR调节异常与多种代谢和神经退行性变相关 疾病，包括核糖体亚基基因杂合性引起的核糖病和夏科氏病 由某些tRNA合成酶突变引起的牙病。ISR信令机制耐人寻味 因为这条途径诱导了应激反应基因的转录，巧合的是，抑制了 信使核糖核酸翻译。ISR在多个水平上抑制mRNA的翻译，包括对翻译的特异性抑制 启动因子eIF2a和eIF-4e。此外，最近的证据表明，mRNAs上的核糖体停滞是 与ISR关联。这些观察提出了一个关于压力反应如何的根本问题 抄本克服了这些多重翻译障碍，在某些情况下，将增加其翻译作为 ISR信令。为了解决这个问题，我们建议使用果蝇的简便遗传工具。ISR监管机构 在这种有机体中，机制是保守的，有一些基因突变可以作为人类的模型 ISR信号异常的疾病。我们对果蝇的初步遗传筛查发现了几个 翻译调节因子被错误地描述为ISR信号传递所需的因素。建立在这些基础上 ，我们将检验中心假说，即新发现的因素具体地调节 翻译应激反应转录本，从而帮助这些mRNA绕过翻译障碍 由ISR强加的。我们将进一步确定新发现的翻译基因的生理意义 果蝇核糖体病和Charcot Marie Tooth病模型的调节机制。一个 该计划的成功实现将促进我们对压力反应的概念性理解 基因表达，并帮助开发针对与ISR相关的疾病的新治疗策略。

Project Summary Cellular stress-responsive mechanisms are essential for cells to adapt to various environmental and physiological conditions. The overall goal of the research program is to understand how cells regulate mRNA translation as part of their stress adaptation process. Of particular interest is a pathway referred to as the Integrated Stress Response (ISR), which is initiated by stress-activated eIF2a kinases that respond to several distinct types of stress. Abnormal regulation of ISR is associated with various metabolic and neurodegenerative diseases, including ribosomopathies caused by heterozygosity in ribosome subunit genes and Charcot Marie Tooth Disease caused by certain tRNA synthetase mutations. The ISR signaling mechanism is intriguing because this pathway induces stress-responsive gene transcription, and coincidentally, suppresses general mRNA translation. ISR inhibits mRNA translation at multiple levels, including the specific inhibition of translation initiation factors, eIF2a and eIF-4E. In addition, recent evidence indicates that ribosome stalling on mRNAs is associated with ISR. These observations raise a fundamental question regarding how stress-responsive transcripts overcome these multiple translational blocks, and in some cases, increase their translation as part of ISR signaling. To address this, we propose to use the facile genetic tools of Drosophila. The ISR regulatory mechanisms are conserved in this organism, and there are genetic mutations that serve as models for human diseases with abnormal ISR signaling. Our preliminary genetic screen in Drosophila has identified several poorly characterized translational regulators as factors required for ISR signaling. Building on these observations, we will test the central hypothesis that the newly identified factors specifically mediate the translation of stress-responsive transcripts, thereby helping those mRNAs to bypass translational blocks imposed by ISR. We will further determine the physiological significances of the newly identified translational regulatory mechanisms in the Drosophila models of ribosomopathies and Charcot Marie Tooth Disease. A successful realization of the proposed plan will advance our conceptual understanding of stress-responsive gene expression, and help develop new therapeutic strategies against diseases associated with ISR.