Epigenetic regulation of kidney regeneration

PROJECT SUMMARY The goal of this K08 Career Development Award proposal is to provide training for Elizabeth Nguyen, MD, PhD, as she establishes her career as an independent academic investigator in the fields of epigenetics and kidney regeneration. As a pediatric nephrologist, Dr. Nguyen helps patients navigate the progression of kidney injury to chronic kidney disease, an irreversible process resulting in immense burden for these families and the healthcare industry. As there is currently no treatment to reverse injury to a fibrotic kidney, her research interest is to identify mechanisms that promote kidney regeneration. To achieve this goal, she is training under the mentorship of Dr. Mark Majesky, whose lab identified that the African spiny mouse evolved the ability to exhibit scar-free kidney regeneration after kidney injury. With her research experience in computational biology and genetics, Dr. Nguyen determined that 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. She generated a fully annotated reference genome for the spiny mouse which enables the epigenomic interrogations she proposes. Her central hypothesis for this proposal is that histone modifications in spiny mice proximal tubular epithelial cells activate gene regulatory networks that promote kidney regeneration in response to ischemic injury. The aims of this proposal will 1) define proximal tubule cell states during kidney regeneration in the spiny mouse, 2) construct gene regulatory networks controlling proximal tubule cell regeneration in the spiny mouse and 3) identify mechanisms critical for kidney regeneration in the spiny mouse, examining the role of the Yap-TEAD pathway as it undergoes histone mediated activation in the spiny mouse kidney as presented in her preliminary data. To achieve these aims, the applicant proposes a career development plan that allows her to gain advanced skills in epigenetics, regeneration biology and models of kidney injury. She has assembled a mentoring team of nationally recognized experts with a history of training successful investigators including her primary mentor, Dr. Mark Majesky (African spiny mice regeneration), and committee members Dr. David Beier (epigenetics of kidney disease), Dr. Steven Henikoff (chromatin profiling methods), Dr. Samir El-Dahr (epigenetics of kidney development), Dr. Shreeram Akilesh (multiomic investigations of kidney injury) and Dr. Hannele Ruohola-Baker (stem cell and regenerative biology). Her training will be complemented by coursework, conferences, and faculty development programming. Her research will be performed at Seattle Children’s Research Institute where key resources include a colony of spiny mice and state-of-the-art genomic technology. Achieving these aims will provide the foundation necessary for her to construct a competitive R01 proposal. Through this proposal, Dr. Nguyen will be well prepared for an independent research career aimed at understanding the epigenetic regulation driving mechanisms of kidney regeneration.