Translational control of stress response signaling

应激反应信号的翻译控制

• 批准号: 10552193
• 负责人: HYUNG D RYOO
• 金额: $ 42.38万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-22 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10552193
• 关键词: Address; Amino Acyl-tRNA Synthetases; Bypass; Cells; Cellular Stress; Charcot-Marie-Tooth Disease; DNA Sequence Alteration; Disease; Drosophila genus; Gene Expression; Genes; Genetic; Genetic Screening; Genetic Transcription; Goals; Heterozygote; Mediating; Messenger RNA; Metabolic Diseases; Modeling; Mutation; Neurodegenerative Disorders; Organism; Pathway interactions; Peptide Initiation Factors; Phosphotransferases; Physiological; Process; Regulation; Research; Ribosomes; Signal Pathway; Stress; Stress Response Signaling; Testing; Transcript; Translational Repression; Translations; biological adaptation to stress; human disease; interest; mRNA Translation; novel therapeutic intervention; programs; ribosomopathy; tool

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.

项目摘要 细胞应激反应机制对于细胞适应各种环境和生理条件是必不可少的。 生理条件。该研究计划的总体目标是了解细胞如何调节mRNA 翻译是他们压力适应过程的一部分。特别令人感兴趣的是一种称为 综合应激反应（ISR），其由应激激活的eIF 2a激酶启动，所述eIF 2a激酶响应几种应激反应。 不同类型的压力。ISR的异常调节与多种代谢和神经退行性病变有关， 疾病，包括由核糖体亚基基因杂合性引起的核糖体病和夏科玛丽氏病 由某些tRNA合成酶突变引起的牙病。ISR信号机制很有趣 因为这一途径诱导应激反应基因转录，并且巧合的是，抑制了一般的 mRNA翻译。ISR在多个水平抑制mRNA翻译，包括特异性抑制翻译 起始因子eIF 2a和eIF-4 E。此外，最近的证据表明，核糖体在mRNA上的停滞是 与ISR有关。这些观察结果提出了一个基本问题，即压力反应如何 转录物克服了这些多个翻译阻断，并且在某些情况下，增加了它们的翻译， ISR信号。为了解决这个问题，我们建议使用果蝇的简易遗传工具。ISR监管 机制在这种生物体中是保守的，并且存在作为人类模型的基因突变。 ISR信号异常的疾病。我们对果蝇的初步基因筛选已经发现了几个 作为ISR信号传导所需因子的翻译调节因子的特征不明确。根据这些 观察，我们将测试中心假设，即新确定的因素专门介导 应激反应转录本的翻译，从而帮助这些mRNA绕过翻译阻断 由ISR施加。我们将进一步确定新发现的翻译的生理意义， 果蝇核糖体病和夏科玛丽牙病模型中的调节机制。一 该计划的成功实施将促进我们对应激反应的概念性理解， 基因表达，并帮助开发针对ISR相关疾病的新治疗策略。