Ciliogenesis defects are central to kidney diseases including cystic kidney disease and nephronophthisis, two major causes of kidney failure in children and adults. The pathogenic mechanisms in ciliopathies remain puzzling however since cyst formation is delayed and highly focal in postnatal conditional PKD knockout models. It is now clear that renal injury significantly exacerbates cystic disease in the context of cilia defect, suggesting that ciliogenic responses may play a key role in tubule regeneration. Our finding that ciliogenic transcription factors FOXJ1 and rfx2 are rapidly induced by injury or mechanical stretch suggests a new paradigm for understanding cystic disease where ciliogenesis may be required for kidney tubule homeostasis and regeneration after injury. We also find that cell stretch is by itself sufficient to stimulate cell proliferation, further implicating mechanosensingin tubule repair. Our data together with the newly established role of purinergic signaling in kidney tubule mechanosensing suggests a strong link between cell stretch, purinergic signaling, proliferation and transcriptional activation of ciliogenesis. The central hypothesis of this proposl is that kidney tubules lacking the ability to stimulate or maintain ciliogenesis, due to cilia gene mutation, cannot undergo proper repair and are predisposed to cyst formation. This proposal aims to identify signaling pathways that control ciliogenesis in response to injury and stretch and directly link these pathways to transcriptional control of FOXJ1 and rfx2. We will also determine whether stretch induced ciliogenesis and cell proliferation are signaled by the same or divergent pathways. The transcriptional responses to stretch and the significance of foxj1 expression to tubule regeneration will also be examined in mouse models. If successful, this work would integrate tubule injury and mechanosensory signaling pathways with transcriptional control of ciliogenesis and reveal new elements of tubule homeostasis central to kidney disease.
Cystic kidney disease remains one of the most common heritable diseases of the kidney for which there is no cure. Studies show that if cyst growth could be arrested, the remaining kidney could continue to function well and support a good quality of life. To treat cystic disease it is essential to learn what normal kidney control system go wrong when cystic disease genes are mutated and how we might intervene to reactivate normal adaptation to kidney injury or stress and stop cyst growth.
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