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My laboratory is interested in mechanisms of Notch signaling, organogenesis, and disease processes. Our mechanistic interests are now focused on Notch activity in the nucleus; we are developing new tools to understand Notch concentration-dependent gene regulation. Our organogenesis efforts are focused on three aspects of renal biology: first, we are investigating the role of Notch signaling in kidney development and adult function. The Notch signaling pathway is a short range communication tool cells in all organs use to resolve local “disputes” (which task is to be performed by what cells) that arise during fate selection among descendents of multipotent cells. Our investigations explain why Alagille syndrome patients have renal malformations and may lead to a treatment strategy. Because many cell types are born from groups of equivalent precursors, Notch is involved in many steps during kidney development, several of which are not yet fully explored.
Second, we are interested in the renal stem cell niche. The mammalian embryos build kidneys with a large surplus of nephrons from a progenitor cell population called the metanephric mesenchyme (MM). Although stem-like in many respects, these embryonic progenitors differentiate en mass when nephron numbers reach a species-appropriate limit (“nephron endowment”) before or shortly after birth. We made a recent breakthrough in our understanding the progenitor niche and the role of FGF molecules in it and we aim to leverage this into practical knowledge about the regulation of nephron endowment.
Third, we have a growing interest in renal aging, especially in the role of Notch in the renal stroma and the mesangium. The importance of renal aging is underscored by the great progress made recently in Alzheimer’s disease research that could translate into longer lifespan in one generation. Since adult kidneys lack stem cells, end stage renal disease is a real threat to longevity. This project has just started and will be a growing area of activity in my lab in coming years.
Raphael Kopan, PhDWilliam K. Schubert Professor of Pediatrics, University of Cincinnati College of Medicine
Director of the Division of Developmental Biology, Cincinnati Children's Hospital Medical Center
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