Project Summary Chronic kidney disease is a public health problem affecting more than 20 million people in the US adult population, and is the 9th leading cause of death. Few drugs other than renin-angiotensin system inhibitors slow the progression of kidney disease, lower mortality rates, or improve quality of life among people. New strategies targeting the early stages of these underlying diseases are fundamentally important to improve outcomes and patient care. To catalyze the development of drugs that are safe and effective for treating kidney diseases, there is a critical need to be able to model human kidney diseases and injury in vitro during preclinical drug development. The complex multicellular architecture and unusual triad of physiological processes characterized by glomerular filtration, tubular secretion and tubular reabsorption, have often limited the ability of whole organism models to fully recapitulate the diversity and manifestations of human disease. Conventional two-dimensional human epithelial cell models do not accurately recapitulate kidney physiology or disease, and microfluidic flow is essential to kidney nephron structure and function, and is an essential component in recapitulating in vivo physiology and pathophysiology. We have developed a three dimensional flow directed ?kidney-on-a-chip? microphysiological system populated with human kidney cells, which has been extensively tested with functional characterization of key component structures of the proximal tubule and the peritubular microvascular network. We are also able to routinely obtain, isolate and characterize relatively pure primary cultures of multiple human kidney cell lineages. In addition, we have developed hydrogels consisting of decellularized human kidney cortical extracellular matrix, and demonstrated phenotypic differences when human kidney cells are grown in this matrix. In addition, we have recently incorporated the use of human pluripotent stem cells coupled with gene editing techniques into our MPS. Our platforms allow for precise control of cellular composition, extracellular matrix, and vascular and tubular geometry and flow. The goal of this application is to model important human kidney diseases and promote identification of safe and effective treatments. To achieve this goal, we have established a multidisciplinary investigative team with expertise in kidney physiology and pathology, cellular and molecular biology, systems pharmacology and toxicology, biomarker discovery and evaluation, biomedical engineering, microfluidics, matrix biology, genomics, computational biology, and biostatistics. If successful, ultimately in vitro models that recapitulate critical aspects of kidney physiological function, response to injury, and repair could contribute greatly to drug discovery and development, and could ultimately enable `virtual clinical trials' for candidate therapeutics.