The failure of many clinical trials in ischemic stroke has led to increasing debate about whether mouse and rat models are valid. We propose that the key for translational stroke research is not whether rodent models can completely predict ALL treatments for human stroke, but how to correctly use cell and animal models for drug development, depending on the mechanisms being targeted. It is likely that when mouse and rat models are compared to human stroke, some targets and mechanisms are the same and some are different. However, there are no systematic studies to assess similarities and differences between mouse and rat cells and models vs human stroke patients. This is the critical gap in translation that we seek to fill. In this project, we will map gene expression after oxygen-glucose deprivation or cerebral ischemia in neurons, astrocytes and microglia from mouse, rats and humans, and build a comparative database of network and pathway responses in all three species.
In Aim 1, we will detect gene expression in primary neurons, astrocytes and microglia from mouse, rat or human under baseline condition and after oxygen-glucose deprivation by gene array, and assess pathways with standard Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analysis. Upregulation or downregulation of pathways will be assessed via z-scores based on MetaBase and Ingenuity databases.
In Aim 2, we will determine gene response in neurons, astrocytes and microglia in peri-ischemic cortex after focal cerebral ischemia in young vs aged as well as normotensive vs hypertensive mouse and rat models for comparison with six validated human stroke patients. mRNA levels and gene pathway responses will again be assessed with gene array and KEGG/GO analysis. Upregulation or downregulation of pathways will be assessed via z-scores based on MetaBase and Ingenuity databases. This project will produce a relational and interactive database of neuronal, astrocytic and microglial gene networks and pathways that respond to oxygen-glucose deprivation in vitro and ischemia in vivo. This comparative database will allow us to (a) compare rodents vs human stroke, (b) compare primary cell culture vs in vivo models, and (c) compare young vs aged animals, and (d) compare normotensive vs hypertensive animals. Ultimately, this relational and interactive database should allow users to interrogate potential mechanisms and targets for translation in cell and rodent stroke models.
Mice and rats are the most commonly used animals for preclinical stroke studies. However, there are no systematic studies to rigorously compare rodent cells and models vs human stroke patients. Our investigation of similarities and differences between mouse and rat vs human brain cells will create a comparative database of neuronal, astrocytic and microglial gene networks and pathways that respond to oxygen-glucose deprivation in vitro and ischemia in vivo, and this database should allow users to interrogate potential mechanisms and targets for translation in cell and rodent stroke models.
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|Du, Yang; Deng, Wenjun; Wang, Zixing et al. (2017) Differential subnetwork of chemokines/cytokines in human, mouse, and rat brain cells after oxygen-glucose deprivation. J Cereb Blood Flow Metab 37:1425-1434|
|Lin, Li; Desai, Rakhi; Wang, Xiaoying et al. (2017) Characteristics of primary rat microglia isolated from mixed cultures using two different methods. J Neuroinflammation 14:101|