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，以确保新药候选物可安全用于人类。因此，临床前模型物种（例如，小鼠、大鼠和猴子）的研究应该通过我们对这些物种与人类之间的生理、解剖和遗传相似性和差异的理解来了解。一个重要的，但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，适应和耐受化学损伤的能力，这些保护途径已经进化为保护细胞免受诸如氧化应激，DNA损伤和蛋白质错误折叠等应激。因此，本项目旨在研究各种应激反应途径的敏感性和活性的潜在种属间差异，这些差异可能影响临床前药物毒性研究对人类的可翻译性。该项目将特别关注肝脏对化学损伤的应激反应，因为肝脏是大多数药物解毒的部位，也是药物毒性的最常见靶点之一。我们将使用公开的和实验性的转录组学数据来建立应激反应相关基因基础表达的种间差异，重点关注新药临床前毒理学研究中常用的种属，沿着人体组织。将使用每个种属的原代肝细胞研究和定量应激反应诱导水平的种属间差异。希望这项研究将有助于选择适当的物种，以提高临床前毒性研究的人类可翻译性。此外，该项目将通过支持药物开发过程中动物使用的改进和最终减少来促进3R。

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.