Unravelling species differences in stress responses to inform the selection, and reduce the use, of animals in preclinical drug safety testing

临床前毒理学研究是药物开发过程的重要组成部分，以确保新药候选药物在人类身上的使用是安全的。因此，在选择临床前模式物种(如小鼠、大鼠和猴子)时，我们应该了解这些物种与人类在生理、解剖学和遗传学上的异同。一个重要的、虽然相对未被探索的方面是，给定物种通过激活各种保护途径来感知、适应和耐受化学伤害的能力，这些保护途径已经进化成保护细胞免受氧化应激、DNA损伤和蛋白质错误折叠等应激。因此，本项目旨在调查可能影响临床前药物毒性研究对人类的可译性的各种应激反应途径的敏感性和活性的潜在物种间差异。该项目将特别关注肝脏对化学侮辱的应激反应，因为肝脏是大多数药物解毒的部位，也是药物毒性最常见的目标之一。我们将使用公开可用的和实验性的转录数据来建立应激反应相关基因基本表达的物种间差异，重点是在新药的临床前毒理学研究中常用的物种以及人类组织。来自每个物种的原代肝细胞将被用来调查和量化物种间应激反应诱导水平的差异。希望这项研究将有助于选择合适的物种，以提高临床前毒性研究的人类可译性。此外，该项目将通过支持改进和最终减少药物开发过程中的动物使用，为3R做出贡献。

Preclinical toxicology studies are a vital component of the drug development process to ensure that new drug candidates are safe for use in humans. As such, the selection of preclinical model species (e.g., mouse, rat, and monkey) should be informed by our understanding of the physiological, anatomical and genetic similarities and differences between these species and humans. One important, though relatively unexplored, aspect is the ability of a given species to sense, adapt to, and tolerate chemical insult via activation of various protective pathways that have evolved to protect cells against stresses such as oxidative stress, DNA damage and protein misfolding. Therefore, this project aims to investigate potential inter-species differences in the sensitivity and activity of various stress response pathways that may influence the translatability of preclinical drug toxicity studies to humans. This project will focus, in particular, on hepatic stress responses to chemical insult as the liver is the site of most drug detoxification and is one of the most common targets of drug toxicity. We will use publicly-available and experimental transcriptomic data to establish inter-species differences in the basal expression of stress response-associated genes, focussing on species that are commonly used during preclinical toxicology studies on new medicines, along with human tissues. Primary hepatocytes from each species will be used to investigate and quantify inter-species differences in the inducible levels of the stress responses. It is hoped that this research will help inform the selection of appropriate species to improve the human translatability of preclinical toxicity studies. Further, this project will contribute to the 3R's by supporting the refinement, and ultimate reduction, of animal use in the drug development process.