The progression of kidney injury to chronic kidney disease is an irreversible process resulting in immense burden for patients and the healthcare industry. As there is currently no treatment to reverse injury to a fibrotic kidney, identifying mechanisms that promote kidney regeneration would have important implications for this significant health burden. The African spiny mouse evolved the ability to exhibit scar-free kidney regeneration after ischemic and obstructive kidney injury. Kidneys of the spiny mouse express the same proteins as the house mouse, but its response to injury is remarkably different, indicating that epigenetic control of gene expression may be the key to its regenerative capabilities. The overall objective of this proposal is to understand how regulation of gene expression differs between spiny and house mice in the setting of kidney injury and regeneration. This project will use single nuclei transcriptomic and chromatin accessibility profiling to identify cell-type specific changes in the spiny mouse during kidney regeneration. As our team has generated the most complete annotated reference genome for the spiny mouse to date using long-read DNA sequencing, we are uniquely well equipped to interpret the genomic data proposed by this research. As the first mammalian model to exhibit restoration of failed kidney function, understanding the unique pathways activated by the spiny mouse as it relates to its regenerative response to kidney injury may provide insight into how kidney regeneration can be activated in humans. These results will have an important positive impact by providing potential mechanisms for the redirection of kidney injury towards regeneration of functional tissue.