The primary cilium, now known as a sensory organelle and a signaling center present in almost all cells, has attracted much attention in the past decade due to its role in a large group of diseases with cystic kidney phenotype. Gene depletion and deletion experiments, and human genetics have shown that either a structural or a functional defect in the primary cilium of kidney epithelial cells leads to cyst formation. The growing group of human diseases with ciliary defects and phenotypes including cystic kidneys, obesity, blindness and mental retardation, are now collectively regarded as ciliopathies. Autosomal dominant polycystic kidney disease (ADPKD), the most common form of ciliopathy, has been a long-standing research focus of my lab. Most studies on ADPKD have focused on how loss of PC1 protein leads to a number of cellular defects in ADPKD though a large number of ADPKD pedigrees have mutations that lead to defective targeting of the mutant proteins to their normal functional sites. At present little is known about the structural determinants for membrane proteins to traffic to the primary cilia and the cellular machinery required for this process. Mechanisms by which full-length PC1 traffics to the primary cilium are unknown. We propose that elucidating the mechanisms by which PC1 traffics to the primary cilia is central to understanding PC1 function and the pathogenesis of ADPKD, as well as to the design of therapeutics for ADPKD. We have designed two aims.
Aim 1 : Elucidate the structural determinants in PC1 responsible for its targeting to the primary cilia;
Aim 2 : Determine the machinery used for PC1 trafficking to the ciliary membrane.

Public Health Relevance

Autosomal dominant polycystic kidney disease (ADPKD) is a leading cause of renal failure, affecting over 600,000 individuals in the United States alone and more than 12 million people worldwide. This research will provide novel insights underlying the mechanisms of the disease by elucidating the membrane trafficking mechanisms of the disease gene products. This research will likely identify new drug targets for the disease.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Kidney Molecular Biology and Genitourinary Organ Development (KMBD)
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Rasooly, Rebekah S
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Brigham and Women's Hospital
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Tilley, Frances C; Gallon, Matthew; Luo, Chong et al. (2018) Retromer associates with the cytoplasmic amino-terminus of polycystin-2. J Cell Sci 131:
Ishimoto, Yu; Inagi, Reiko; Yoshihara, Daisuke et al. (2017) Mitochondrial Abnormality Facilitates Cyst Formation in Autosomal Dominant Polycystic Kidney Disease. Mol Cell Biol :
Shen, Xiujin; Jiang, Hong; Ying, Meike et al. (2016) Calcineurin inhibitors cyclosporin A and tacrolimus protect against podocyte injury induced by puromycin aminonucleoside in rodent models. Sci Rep 6:32087
Wu, Xudong; Indzhykulian, Artur A; Niksch, Paul D et al. (2016) Hair-Cell Mechanotransduction Persists in TRP Channel Knockout Mice. PLoS One 11:e0155577
Wu, Yong; Xu, Jen X; El-Jouni, Wassim et al. (2016) G?12 is required for renal cystogenesis induced by Pkd1 inactivation. J Cell Sci 129:3675-3684
Yao, Gang; Luo, Chong; Harvey, Michael et al. (2016) Disruption of polycystin-L causes hippocampal and thalamocortical hyperexcitability. Hum Mol Genet 25:448-58
Freedman, Benjamin S; Brooks, Craig R; Lam, Albert Q et al. (2015) Modelling kidney disease with CRISPR-mutant kidney organoids derived from human pluripotent epiblast spheroids. Nat Commun 6:8715
Su, Xuefeng; Wu, Maoqing; Yao, Gang et al. (2015) Regulation of polycystin-1 ciliary trafficking by motifs at its C-terminus and polycystin-2 but not by cleavage at the GPS site. J Cell Sci 128:4063-73
Antignac, Corinne; Calvet, James P; Germino, Gregory G et al. (2015) The Future of Polycystic Kidney Disease Research--As Seen By the 12 Kaplan Awardees. J Am Soc Nephrol 26:2081-95
DesRochers, Teresa M; Kimmerling, Erica Palma; Jandhyala, Dakshina M et al. (2015) Effects of Shiga toxin type 2 on a bioengineered three-dimensional model of human renal tissue. Infect Immun 83:28-38

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