Stefan Somlo MD
C. N. H. Long Professor of Medicine (Nephrology) and Professor of Genetics; Chief, Section of Nephrology
Genetic kidney and liver disease; Cilia function in tissue homeostasis; Polycystin function
- Determinants of polcystin-1 (Pkd1) and polycystin-2 (Pkd2) function;
- Functional relationship of the isolated polycystic liver disease genes, Sec63 and Prkcsh, to cyst formation;
- Role of MAPK/ERK pathway in polycystic kidney disease;
- Role of the recessive PKD gene, Pkhd1, in tissue polarity and kidney disease
The goal of our laboratory is to understand the human polycystic diseaseas 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 disovering 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 five 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 understandng into specific treatments for patients and families affected by polycystic kidney and liver diseases.
Extensive Research Description
The primary focus of our laboratory is understand the pathogenesis of polycystic kidney and liver diseases (ADPKD, ADPLD, 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 organization. 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 the pathogenesis of PKD beginning with discovery of human disease genes for dominant PKD (PKD2), recessive PKD (PKHD1) and two genes for isolated dominant polycystic liver disease (PRKCSH, SEC63). Our lab now seeks to define the cellular pathways in which the PKD-gene products function and to translate these findings to treatment for PKD. A central principle of our current approach is need to address disease processes affecting three dimensional tissue organization and polarity using in vivo vertebrate 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 PKD in vivo. Specific projects include dissection of the molecular pathways of trafficking of PKD1 and PKD2, to cilia, the inter-relationship of cilial function with the ER proteins PRKCSH and SEC63, the regulation of the PKD2 Ca2+ channel, the role of Ca2+ signaling in PKD and the intersection of tissue polarity (also called planar cell polarity) with PKD pathways.
We continue to keep in focus the need to develop principles for therapy in PKD that are based on basic science discoveries and to this end have focused on defining the cellular features of cyst cells (e.g., proliferation, cystoskeletal features, intercellular adhesion properties, etc.) as means of defining targets for therapy.