Polycystic kidney disease (PKD) is characterized by the formation of cysts, which originate from the epithelial tubules of the nephron. Progressive growth of the cysts causes damage and loss of functional nephrons, ultimately leading to end-stage renal failure. The pathophysiology of PKD is incompletely understood, and only one FDA-approved treatment (tolvaptan) exists today. Long noncoding RNAs (lncRNA) ? defined by a length >200 nucleotides and absence of a long open reading frame ? are a class of non-protein-coding RNAs implicated in a range of diseases. The nature and extent of involvement of lncRNAs in PKD was not previously investigated. Utilizing two independent PKD mouse models, the applicant identified Hoxb3os, a highly conserved lncRNA, which was downregulated in mouse and human ADPKD. Deletion of Hoxb3os in kidney cells resulted in increased phosphorylation of mTOR and its downstream targets. Consistent with activation of mTOR signaling, Hoxb3os mutant cells displayed increased oxidative phosphorylation, increased cell proliferation, and decreased autophagy. The Hoxb3os mutant phenotype was partially rescued upon re- expressing wild-type Hoxb3os in knockout cells. Importantly, deletion of Hoxb3os in wild-type mice recapitulated the in vitro molecular phenotype and resulted in increased mTOR phosphorylation and subsequent increased cell proliferation, and defective autophagy. The overarching hypothesis for this K01 project is that downregulation of Hoxb3os exacerbates cyst formation and/or disease progression by dysregulating multiple pathways, including mTOR signaling. To test this hypothesis, the applicant will decipher the mechanism by which Hoxb3os inhibits mTOR signaling, identify novel Hoxb3os-regulated pathways, and determine the contribution of Hoxb3os to cyst formation in a mouse model of ADPKD. The applicant has assembled an interdisciplinary team of senior investigators to guide the proposed research and provide mentorship during his transition to independence. He will have full access to the University's shared resources (mouse genetics laboratory, high-throughput sequencing, mass spectrometry and proteomics, bioinformatics). The applicant's training plan includes mentorship in core technique and concepts, generating and analyzing data, publishing and presenting results, completing coursework (in mouse genetics, biostatistics, RNA biology, computational methods, bioinformatics), and developing other requisite skills (in leadership, grant proposal development) needed to thrive as an independent investigator. Results from the proposed studies will form the basis for an R01 application to be submitted in the fourth year of this career development award. The applicant's long-term goal is to dedicate his career to advancing basic and translational research on cystic kidney disease as an independent investigator at an academic institution. As a kidney researcher with a deep interest and proven track record in molecular biology, he is uniquely positioned to answer the questions set forth in this proposal and to rapidly advance the mechanistic understanding of lncRNAs in PKD pathogenesis

Public Health Relevance

Preventing the formation or slowing the growth of kidney cysts is crucial to the long-term survival and quality of life of patients with polycystic kidney disease (PKD). The proposed research is broadly relevant to public health because it will be the first study to identify a lncRNA (Hoxb3os) that directly binds to and inhibits mTORC1 activity. Results from this study will provide genetic proof-of-concept for future studies that focus on targeting lncRNAs as a treatment option in PKD.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Scientist Development Award - Research & Training (K01)
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Kidney, Urologic and Hematologic Diseases D Subcommittee (DDK)
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Rankin, Tracy L
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University of Minnesota Twin Cities
Internal Medicine/Medicine
Schools of Medicine
United States
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