Genetic components of podocyte differentiation and disease – GenPod

The mammalian kidney is a central cardiovascular organ that fulfils pleiotropic functions in the body including blood filtration, control of blood pressure, salt concentrations and pH. Renal diseases are on the rise and 1 out of 10 people is expected to develop some form of renal disorder during their life. Research to uncover the molecular basis of renal disease and to develop new therapies is therefore of utmost importance from a health and socioeconomic point of view.
One common form of renal disease is focal segmental glomerulosclerosis (FSGS). FSGS is a histologic pattern of renal damage that is associated with a spectrum of primary (hereditary and immune-mediated) and secondary glomerular diseases (diabetes, HIV etc), including isolated proteinuria and steroid-resistant nephrotic syndrome. Studies of rare hereditary forms of FSGS have been instrumental to unravel the pathophysiology of this disease and have demonstrated the crucial role of the podocyte, a highly differentiated glomerular epithelial cell, in the development and function of the glomerular filtration barrier. Recent years have seen the identification of a number of genes mutated in these subsequently named hereditary podocytopathies, but despite these advances the molecular basis for more than 50% of patients remains unknown.
The partners in the present project have a long-standing interest in podocyte biology and have made major contributions to our present understanding of glomerular function and the identification of genes underlying glomerulosclerosis. During the past few years the partners have isolated a range of novel podocyte specific genes that are deregulated or mutated in glomerular disorders. Aim of the present project is to build on these achievements and 3 major objectives have been delineated.
Firstly, we will study the molecular processes leading to podocyte differentiation and disease. Using in vitro studies we will address the role of the INF2/Cdc42/MAL2 complex in vesicular transport of proteins to the slit diaphragm and its interaction with the cytoskeleton. We will analyse the function of the membrane associated guanylate kinase MAGI2, which we have recently shown to be required for normal foot process formation and evaluate its potential function in podocyte signalling pathways. Moreover, we will determine the function of the recently identified protein THSD7A in maintaining podocytes in a differentiated state and its potential role in suppressing integrin signalling.
Secondly, we will use ChIP-Seq analysis to identify a molecular code determining podocyte identity. This will involve the identification of genome wide binding sites of key transcription factors required for podocyte differentiation coupled with podocyte specific analysis of epigenetic histone marks characteristic for active and repressed genes. Data obtained will be mined for key regulatory elements and transcriptional networks will be established.
Finally, we will employ state of the art sequencing techniques to identify molecular defects in patients suffering from FSGS. To achieve this goal we will exploit our well-characterized and unique patient cohorts coupled to exome sequencing. Genes that carry mutations will be further analysed using molecular and genetic studies to determine their role within the podocyte.
Taken together this project will provide important insights into the molecular pathways underlying glomerular differentiation and the processes occurring during FSGS. In addition the results will be an important contribution for patient diagnosis and genetic counselling and may in the long run help to develop new therapeutic interventions.