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Stefan Somlo, MD

C. N. H. Long Professor of Medicine (Nephrology) and Professor of Genetics; Chief, Section of Nephrology

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Stefan Somlo, MD

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Research Summary

The goal of our laboratory is to understand the human polycystic diseases of the kidney and liver so that specific treatments can be developed. As a group, these diseases result in the progressive disruption of the normal structure and function of the affected organs leading to the symptoms that patients experience. To achieve our goal, we begin by discovering the genes responsible for these diseases in patient families and then proceed to studying the functions of the protein products of these genes in cells and tissues. We have discovered nine genes for the polycystic diseases so far and we are working to understand how they normally work together to prevent disease from occurring. As we understand more and more about the normal functions of these human disease genes, we expect to successfully translate this understanding into specific treatments for patients and families affected by polycystic kidney and liver diseases.

Specialized Terms: Genetic kidney and liver disease; Cilia function; Polycystin function

Extensive Research Description

The primary focus of our laboratory is understand the pathogenesis of polycystic kidney and liver diseases (ADPKD, PCLD, ARPKD). These diseases are the most prominent among a larger group of pleiotropic human genetic diseases which share fibrocystic deterioration of the kidney and liver as a key phenotypic feature and whose pathogenesis is related to the functioning of the primary cilium and basal body complex. Study of these diseases have uncovered the central role of cilia in novel signaling pathways and in establishing and maintaining three dimensional tissue structure. Therefore, understanding the mechanism of polycystic diseases will not only shed light on diseases for which there are no therapies currently but will also uncover general principles of the functioning of cilia in human biology.

We have taken a longitudinal approach to understanding the pathogenesis of polycystic kidney disease beginning with discovery of human disease genes for ADPKD (PKD2), ARPKD (PKHD1) and six genes for isolated dominant polycystic liver disease. While we continue our gene discovery efforts using next generation sequencing approaches (whole exome sequencing), our lab now seeks to define the cellular pathways in which the ADPKD-gene products (PKD1, PKD2) function and to translate these findings to treatments for ADPKD. A central principle of our current approach is need to address disease molecular processes impacting polycystic kidney and liver diseases using novel genetically engineered mouse models. To this end, we have developed a series of conditional and inducible mouse models of the relevant human disease genes and combined them with bacterial artificial chromosome (BAC) transgenic lines modified by recombineering to define the mechanisms of ADPKD, PCLD and ARPKD in vivo. Specific projects include dissection of the molecular pathways of trafficking of PKD1 and PKD2, to cilia, the inter-relationship of cilia function with PKD1 and PKD2 signaling, and the interaction of polycystic diseases with the unfolded protein response. We continue to keep in focus the need to develop principles to guide therapy in ADPKD based on basic science discoveries.

Coauthors

Research Interests

Cilia; Genetics; Kidney Diseases; Liver Diseases; Nephrology; TRPP Cation Channels

Selected Publications

Clinical Trials

ConditionsStudy Title
Diseases of the Cardiovascular System; Diseases of the Kidney & Urinary Tract; Genetics - AdultGenetic Determinants of Aneurysms in Autosomal Dominant Polycystic Kidney Disease
Diseases of the Digestive System - Liver; Genetics - AdultGenetic Studies of Polycystic Livers
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