Assistant Professor of Medicine (Nephrology); Course Director, Noon Conference Series, Internal Medicine: Nephrology
Inherited Diseases of the Kidney
Polycystic kidney diseases (PKD) are single gene disorders of kidney structural homeostasis that causes fluid-filled cysts to form and expand in the kidneys. The cysts enlarge and cause secondary processes, which eventually harm kidney function and lead to chronic kidney disease. The liver is also affected by cysts originating from the bile ducts and, while liver function is typically preserved, the cysts can sometimes grow so large that they cause symptoms. Kidney and liver cysts can occur alone or together in families, and at least 10 different genes have been identified that cause these human diseases. However, amongst these genes, only PKD1 and PKD2 are known to result in kidney failure due to PKD.
Dr. Somlo’s research primarily focuses on discovery of the molecular mechanisms of polycystin-1 and polycystin-2 function, the gene products of PKD1 and PKD2, respectively. These proteins have a largely unknown but critical function in cilia, solitary hair-like projections on the apical (luminal) aspects of kidney tubule cells that are critical to maintaining kidney structural homeostasis. The lab uses an extensive and expanding group of engineered mouse models coupled with cell biological and biochemical analyses and studies based on transcriptomic sequencing approaches to discover and validate critical functional components of polycystin and cilia function in PKD. Dr. Somlo’s lab provided the initial evidence for the causative role of the two-hit mechanism in cyst formation in mouse models; defined the in vivo functional inter-relationship amongst the genes for PKD and the genes for isolated polycystic liver disease (PCLD); and discovered the paradoxical suppressive role of cilia inactivation on cyst growth in genetic models of ADPKD based on PKD1 and PKD2. His lab has identified candidate molecular drivers of cyst growth that are selectively activated by loss of polycystins in the presence of intact cilia. Most recently, the lab has applied translating ribosome affinity purification (TRAP) RNA sequencing to the latter models to define the in vivo transcriptional signature of PKD1-deficient cells destined to form cysts.
Dr. Cantley’s lab focuses on the mechanism of tubular growth and maintenance and how those are disordered in the absence of polycystin expression. His group demonstrated that macrophages surround newly developing cysts in mouse models and accelerate radial expansion of the tubule. They have shown that this effect is driven by tubular cell overproduction of Mcp1 and the sequential activation of macrophages as initially proinflammatory and causing tubule remodeling, followed by alternative activation promoting increased tubular cell proliferation.
Dr. Besse's lab focuses on identifying novel disease genes for genetic kidney and liver diseases, and using such genes as entry points for investigation of disease mechanism and therapeutic targets. Dr. Besse orchestrates two human protocols to enroll patients with suspected genetic tubulointerstitial or polycystic kidney disease for whom clinical genetic testing was unrevealing, or who have the mechanistically-related polycystic liver disease phenotype. The lab is currently investigating the role of several genes encoding proteins in the endoplasmic reticulum in which mutations are rare causes of polycystic and/or tubulointerstitial phenotypes.
Dr. Caplan’s lab focuses on proteins involved in ion transport, as well as on the proteins associated with polycystic kidney disease. Polycystic kidney disease is caused by mutations in genes encoding polycystin-1 and 2. We have found that polycystin-1 undergoes a proteolytic cleavage that releases its cytoplasmic C terminal tail. This fragment is transported to the nucleus, where it appears to modulate several signaling pathways. This behavior may account for the capacity of polycystin-1 to participate in communication between the cell surface and the nucleus.
C. N. H. Long Professor of Medicine (Nephrology) and Professor of Cellular And Molecular Physiology; Vice Chair, Research; Co-director of Education, Yale Center for Clinical Investigation
C. N. H. Long Professor of Cellular And Molecular Physiology and Professor of Cell Biology; Chair, Cellular and Molecular Physiology
Professor Adjunct; Medical Director, Outpatient Dialysis, Nephrology; Director, Nephrology Clinical Trials Program, Nephrology
C. N. H. Long Professor of Medicine (Nephrology) and Professor of Genetics; Chief, Section of Nephrology