Cilia; Genetics; Homeostasis; Kidney Diseases; Liver Diseases; Nephrology; TRPP Cation Channels
Physiology of Human 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.
Specialized Terms: Genetic kidney and liver disease; Cilia function in tissue homeostasis; Polycystin function
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.
- 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
- Sec63 and Xbp1 regulate IRE1α activity and polycystic disease severity Fedeles SV, So JS, Shrikhande A, Lee SH, Gallagher AR, Barkauskas CE, *Somlo S, *Lee AH. (2015), J Clin Invest. 2015 May;125(5):1955-67. doi: 10.1172/JCI78863. Epub 2015 Apr 6
- Altered trafficking and stability of polycystins underlie polycystic kidney disease. Cai Y, Fedeles SV, Dong K, Anyatonwu G, Onoe T, Mitobe M, Gao JD, Okuhara D, Tian X, Gallagher AR, Tang Z, Xie X, Lalioti MD, Lee AH, Ehrlich BE, Somlo S. J Clin Invest, 124:5129-44.
- Loss of cilia suppresses cyst growth in genetic models of autosomal dominant polycystic kidney disease. Ma M, Tian X, Igarashi P, Pazour GJ, Somlo S. Nature Genet., 45:1004–1012.
- Fedeles SV, Tian X, Gallagher AR, Mitobe M, Nishio S, Lee SH, Cai Y, Geng L, Crews CM, Somlo S: A genetic interaction network of five genes for human polycystic kidney and liver diseases defines polycystin-1 as the central determinant of cyst formation. Nat Genet 43:639-647, 2011
- Nishio S, Tian X, Gallagher AR, Yu Z, Patel V, Igarashi P, Somlo S: Loss of oriented cell division does not initiate cyst formation. J Am Soc Nephrol 21:295-302, 2010
- Geng L, Boehmerle W, Maeda Y, Okuhara DY, Tian X, Yu Z, Choe CU, Anyatonwu GI, Ehrlich BE, Somlo S: Syntaxin 5 regulates the endoplasmic reticulum channel-release properties of polycystin-2. Proc Natl Acad Sci U S A 105:15920-15925, 2008
- Shibazaki S, Yu Z, Nishio S, Tian X, Thomson RB, Mitobe M, Louvi A, Velazquez H, Ishibe S, Cantley LG, Igarashi P, Somlo S: Cyst formation and activation of the extracellular regulated kinase pathway after kidney specific inactivation of Pkd1. Hum Mol Genet 17:1505-1516, 2008