Epigenetic Regulation of Kidney Regeneration: The progression of kidney injury to chronic kidney disease is an irreversible process, placing an immense burden on patients and the healthcare system. With no treatments available to reverse a scarred, or fibrotic, kidney, our research focuses on identifying mechanisms that could promote kidney regeneration, offering a new path forward for this significant health challenge. Our work is centered on the African spiny mouse, a unique mammal with the remarkable ability to regenerate kidney tissue after injury. By generating a fully annotated reference genome for this animal, we discovered that while it expresses the same proteins as the common house mouse, its response to kidney injury is profoundly different. These differences are likely directed by epigenetic control of gene expression. A major focus of our investigation is on nucleosomes, which are complexes that wrap DNA and control which genes can be accessed and expressed. This regulation is governed by modifications to the histone proteins that make up the nucleosomes. These histone modifications play a critical role in dynamic cellular processes like development and disease. Our research aims to understand how histone modifications in the spiny mouse activate unique gene regulatory networks that promote kidney regeneration following injury. We are working to define the specific gene programs that are uniquely active in the spiny mouse. We are also exploring how a specific histone modifications drives the different gene pathways activated in both the house mouse and the spiny mouse after injury. As the first mammalian model to demonstrate restoration of failed kidney function, the spiny mouse offers an unprecedented opportunity. By understanding its unique regenerative pathways, we hope to provide insights into how kidney regeneration can be activated in humans, ultimately leading to therapeutic strategies that can redirect kidney injury toward the repair of functional tissue.
Advancing Genetic Diagnosis in ADPKD: In collaboration with Drs. Alex Keefe and Danny Miller, we are pioneering a novel approach to detect “hidden” genetic variants in cystic kidney disease, specifically Autosomal Dominant Polycystic Kidney Disease (ADPKD). Despite ADPKD being the most common inherited kidney disease, standard genetic testing often fails to identify the molecular cause in a significant number of patients. This is due to the large, complex nature of genes like PKD1 and PKD2, which are characterized by high GC content, homologous pseudogenes, and the potential for somatic mosaicism. Our research proposes to overcome these challenges by combining Long-Read Sequencing (LRS) with DNA extracted from urine. LRS is an emerging technology capable of reading DNA molecules thousands of bases long, making it uniquely suited for detecting structural variants and analyzing the complex genomic regions often missed by current short-read methods. The use of urine, which contains DNA from kidney cells, offers a unique, non-invasive “liquid biopsy” to obtain tissue-specific genetic information. This innovative approach is expected to significantly increase the diagnostic rate for cystic kidney disease and reduce barriers to testing. If LRS can accurately detect genetic variants from a simple urine sample, this could establish a new gold standard for obtaining tissue-specific genetic information from individuals with kidney disease, ultimately leading to improved patient outcomes.