Joseph V. Bonventre, MD, PhD
Dr. Bonventre is Chief of the Renal Unit and Chief of the Engineering in Medicine Division at Brigham and Women's Hospital and has had a long-standing interest in various aspects of cellular injury and repair mechanisms in the kidney with a special emphasis on the role of inflammation, biomarkers and stem cells. He has established the origin of the epithelial cells that repair the kidney after injury as dedifferentiated surviving proximal tubule cells. He was the first to describe the role of proximal tubule cell cycle arrest in the maladaptive fibrosis that can occur after severe injury leading to chronic kidney disease. He discovered and characterized Kidney Injury Molecule-1 (KIM-1) as the most highly upregulated protein in the proximal tubule after injury to the kidney of various types. Kim-1 expression converts the proximal tubule cell to a phagocyte. Kim-1 is has been qualified by the FDA and European Medicines Agency as a sensitive and specific urinary biomarker for kidney injury in preclinical studies of nephrotoxicity. He published the first demonstration of creation of an iPS cell line from a kidney disease, polycystic kidney disease, which has an abnormality with plausible significance with respect to the etiology of the disease. iPS cells generated from fibroblasts of humans with autosomal dominant PKD had reduced ciliary levels of polycystin-2 which could be rescued in iPS-derived hepatoblasts by overexpression of polycystin-1. This work opened up the possibility to conduct "kidney clinical trials in a dish" with patient specific cells that can by evaluated for efficacy of potential therapeutic agents. He developed a rapid and efficient process by which human iPS and ES cells can be differentiated into intermediate mesoderm and subsequently form organoids- multisegmented kidney structures containing glomerular-like cell clusters surrounded by a epithelial layer mimicking Bowman's capsule, flowing into a continuous tubular structure with properties of proximal tubule, followed by loop of Henle and distal convoluted tubule. These proximal tubule structures have secretory function and specificity of response to toxins. KIM-1 is expressed with nephrotoxins only in proximal tubule segments. We supplemented this work with studies using genome editing (CRISPR) approaches to inactivate genes to study PKD and the function of podocalyxin, a glomerular podocyte protein, to regulate cell-cell interactions.