Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a common life threatening disease characterized by progressive renal tubules dilatation, bilateral formation and expansion of multiple septate fluid-filled cysts that increasinly compress the renal parenchyma, thus altering the kidney architecture and gradually impairing organ function. To date there is no cure for ADPKD, which remains a main cause of end stage renal disease. Mechanisms underlying ADPKD pathogenesis are complex and not completely understood. The disease is caused by germline mutations in the PKD1 or PKD2 genes, which code for polycystin-1 (PC1) or polycystin-2 (PC2), respectively. PC1 and PC2 intersect in various signaling pathways that converge on largely overlapping clinical manifestations. In recent years, the importance of the cilium in renal development has prompted intense investigation of the different ciliary pathways involved in cytogenesis. However, the cilia hypothesis alone is insufficient to explain the more severe cytogenetic phenotypes associated with the loss of polycystins. Cystogenic events may occur that are independent of or preceding ciliary defects, although the nature of these early triggers remains unclear. Alteration of the extracellular matrix (ECM) has long been recognized as a distinctive feature of ADPKD epithelia, and the cystogenic process is associated with increased expression of integrins. Our previous work has shown the important role of integrin-?2?1 in the survival of PC1 knockdown cells. We recently showed that integrin-?1 is a previously unrecognized key mediator of cystic pathogenesis. The working hypothesis of this application is that ECM-Integrin-PC1 interactions are important in the cystic pathways of both ciliary and non-ciliary origin. This hypothesis will b tested both in vitro and in vivo. Specifically, we will determine how Integrin-?1 functions are affected by PC1 through the comparative analysis of the proteins that participate in the integrin-?1 activation pathway in normal and cystic cells, and will determine the role of integrin-?1 in te trafficking and cross-activation of the EGF receptor pathway in cell depleted of PC1. To test the role of integrin-?1 in renal cytogenesis from ciliary defects we will analyze the effects of the deletion of integrin-?1 in genetic models of renal cystic disease that allow the conditional deletion of Pkd1, IFT20, and IFT88. Finally, we will examine the function of integrin-?1 on disease progression and the possibility to ameliorate the cystic phenotype using a small molecule to target integrin-?2?1. The results of these studies will provide insights on the function of integrin-?1 in ADPKD pathogenesis and whether cystogenic mechanisms of different genetic origin may converge onto integrin-?1 signaling pathway. Importantly, this work will determine and whether the integrin pathway can be pharmacologically targeted to slow the progression of ADPKD.
There is currently no available cure for Autosomal Dominant Polycystic Kidney Disease (ADPKD), which is the fourth cause of end stage renal disease. The development of effective therapies is hampered by the incomplete understanding of the pathogenetic mechanism of the disease. These proposed studies explore a newly identified pathway of ADPKD pathogenesis that can provide novel therapeutic targets.
|Revenkova, Ekaterina; Liu, Qing; Gusella, G Luca et al. (2018) The Joubert syndrome protein ARL13B binds tubulin to maintain uniform distribution of proteins along the ciliary membrane. J Cell Sci 131:|