Cystic kidney diseases are characterized by hyperproliferation of normally quiescent renal epithelial cells, which profoundly alter the organ architecture and impair renal function over time. The slow accumulation of cysts throughout adult life highlights the progressive aspect of the disease and, in theory, provides a relatively large window of time to treat affected individuals. However, there are as yet no effective molecular therapies that successfully halt or slow disease progression. As such, understanding the underlying cellular and molecular defects that contribute to the disease progression is critica in developing an effective therapeutic strategy. The central problem addressed in the proposed research is to define how defects in the biogenesis and function of an essential microtubule-based organelle, the centrosome, contributes to the cystic transformation of renal epithelial cells. The centrosome, along with its associated structure the cilium, act together as a cellular signaling center to organize and regulate the activity of important developmental signaling pathways including Hedgehog, mTOR, Notch and Wnt, among others. Mutations in proteins that localize and function through the centrosome-cilium complex cause human disease conditions termed ciliopathies, which include polycystic kidney disease and nephronophthisis. Recent studies have noted the presence of ectopic centrosomal structures (meaning too many centrosomes per cell) in renal epithelial cells isolated from patients and animal models of polycystic kidney disease. Surprisingly, this phenotype has been mostly ignored, and considered a potential secondary effect of cystic cell transformation and proliferation. However, we believe that abnormal centrosome biogenesis may play an important causal role in the pathogenesis of the disease, and our preliminary data support this theory. We recently demonstrated that the formation of ectopic centrosomes in kidney epithelial cells results in aberrant ciliary signaling, disrupted epithelial cell polarity, migration, and division. These are characteristic of cellular transformations that occur during cyst formation and progression, and suggest a potentially novel mechanism (the formation of ectopic centrosomes) by which cystogenesis may occur. In addition, using novel genetic mouse models with which we can alter centrosome biogenesis in vivo we show, for the first time, that the formation of ectopic centrosomes indeed leads to rapid cystogenesis. This exciting discovery supports our hypothesis that ectopic centrosome biogenesis alone is sufficient to trigger cyst formation and growth, even in the absence of mutations in cystic genes. The proposed experiments will determine the mechanism(s) by which aberrant centrosome biogenesis leads to the development and growth of renal cysts in vivo, and test whether inhibiting the formation of these ectopic centrosomes can halt or slow cystogenesis. These studies will help in understanding the fundamental cellular events that trigger cystogenesis, and characterize a potentially new therapeutic target for treatment of cystic kidney disease.
The centrosome is an essential component of the microtubule cytoskeleton in mammalian cells, and plays important roles in regulating a host of fundamental cellular processes. Defective centrosome assembly and organization can have adverse effects on cell division, migration and signaling. These cellular defects ultimately result in a number of human disease syndromes. The goal of this proposal is to understand how changes in the structure and function of centrosomes disrupt normal kidney development and cause cystic kidney disease.
|Trott, Josephine F; Hwang, Vicki J; Ishimaru, Tatsuto et al. (2018) Arginine reprogramming in ADPKD results in arginine-dependent cystogenesis. Am J Physiol Renal Physiol :|
|Dionne, Lai Kuan; Shim, Kyuhwan; Hoshi, Masato et al. (2018) Centrosome amplification disrupts renal development and causes cystogenesis. J Cell Biol 217:2485-2501|
|Betleja, Ewelina; Nanjundappa, Rashmi; Cheng, Tao et al. (2018) A novel Cep120-dependent mechanism inhibits centriole maturation in quiescent cells. Elife 7:|
|Wambach, Jennifer A; Wegner, Daniel J; Yang, Ping et al. (2018) Functional characterization of biallelic RTTN variants identified in an infant with microcephaly, simplified gyral pattern, pontocerebellar hypoplasia, and seizures. Pediatr Res 84:435-441|
|Potter, C; Razafsky, D; Wozniak, D et al. (2018) The KASH-containing isoform of Nesprin1 giant associates with ciliary rootlets of ependymal cells. Neurobiol Dis 115:82-91|
|Potter, Chloe; Zhu, Wanqiu; Razafsky, David et al. (2017) Multiple Isoforms of Nesprin1 Are Integral Components of Ciliary Rootlets. Curr Biol 27:2014-2022.e6|
|Hwang, Vicki J; Zhou, Xia; Chen, Xiaonan et al. (2017) Anticystogenic activity of a small molecule PAK4 inhibitor may be a novel treatment for autosomal dominant polycystic kidney disease. Kidney Int 92:922-933|