| Project Detail |
Dysfunction of cilia can lead to organ laterality defects during development, skeletal abnormalities, mental disabilities, metabolic syndromes, and chronic kidney diseases such as nephronophthisis (NPHP) and polycystic kidney diseases (PKD). In renal tubules, primary cilia are important to sense the flow of urine to regulate their response when that flow is blocked by tissue damage. Embryological studies on the development of organ laterality revealed that flow sensing by primary cilia depends on the RNA-binding protein Bicaudal-C1 (Bicc1). Therefore, we hypothesize that a similar function of Bicc1 in cilia signal transduction is essential to protect renal tubules against polycystic kidney diseases. The goal of this project is to profile the changes in cyst-promoting pathways and in the aggressiveness of PKD after kidney-specific Bicc1 deletion in different nephron segments and at different stages, and to elucidate how Bicc1 links the regulation of specific target mRNAs to flow stimulation of primary cilia. Specifically, our aims are:1. Assess the relative contributions of Bicc1 in different nephron segments to mortality after early onset of PKD-like disease and in adult kidneys. 2. Assess the influence of Bicc1 on renal gene expression and on the protection against tissue injury by microcrystals of certain metabolites.3. Develop imaging tools to test whether and how Bicc1 RNP dynamics are regulated by flow and/or cilia to control protein synthesis.The proposed studies and novel tools to analyse flow sensing by Bicc1 will be important to accelerate the discovery of therapeutic opportunities for diseases linked to cilia signalling defects in PKD patients and beyond. |
