This proposal describes a 5 year training program for Dr. Eva Furrow. Dr. Furrow is a veterinarian (Small Animal Internal Medicine specialist) and researcher in Comparative Medical Genetics at the University Of Minnesota (UMN). Her research uses the dog as a model to ascertain susceptibility genes for urolithiasis (urinary stones disease). She previously identified a causal mutation for a rare stone type and is now investigating the most common human stone type: calcium oxalate (CaOx). The UMN has a reputation of research excellence in comparative medicine. Dr. Furrow's primary mentor, Dr. Jody Lulich, is a professor and chair of nephrology/urology at the College of Veterinary Medicine. He is the co-director of the Urolith Center (the world's largest veterinary stone center) and is renowned for his stone research. Her co-mentors, Drs. Jim Mickelson and Ned Patterson are professors in genetics and run the Canine Genomics Laboratory. Her final co-mentor, Dr. Michael Romero, is a professor in physiology and a member of the O'Brien Urology Center at Mayo Clinic. He is an expert on transporter physiology and has extensive experience with animal models. Dr. Furrow's team will provide high caliber mentoring to enable her to become a productive, independent research professor. The K01 project will result in several publications, teach Dr. Furrow techniques that will enhance her future research potential, and provide new directions to pursue in stone research. Dr. Furrow will also train in grant writing and utilize thee skills to procure independent research funding. CaOx urolithiasis is a significant health problem affecting 10% of the population. There is a substantial inherited component to stone risk, but susceptibility genes have largely evaded identification. Dogs, unlike rodents, offer a spontaneous model of CaOx urolithiasis. Dr. Furrow's recent work in the UMN Canine Genomics Laboratory identified a zinc (Zn) solute carrier gene, Slc39a10, that is significantly associated with CaOx urolithiasis risk in dogs. This is an exciting candidate gene in light of growing literature that supports a role of Zn in the initiation of stone formation. Additionally, preliminary data from a fly model demonstrates that renal knockdown of Slc39a10 increases CaOx stone volume; similar results are found with the exposure of fly kidney tubules to a Zn-containing bathing solution. The proposed project will study the role of Zn transporters and dietary Zn in CaOx urolithiasis. The first objective is to investigate the mechanism by which canine Slc39a10 causes CaOx stone risk. This will be accomplished by completing variant discovery for the gene, determining if gene expression is altered, and analyzing urinary Zn concentrations. The second objective is to use a fly model to test the effects of genetic manipulation of Zn transporters and dietary Zn supplementation on CaOx stone formation. This project will provide insight on the role of Zn in the pathogenesis of kidney stones and will highlight genes for investigation in humans. The novel data is expected to lead to the future development of innovative preventative measures.

Public Health Relevance

Calcium oxalate (CaOx) urinary stones are a common and painful condition affecting 10% of people. Analysis of genetic data from dogs that naturally suffer from this disease has identified a gene that is associated with CaOx stone risk. The proposed research will investigate the mechanism by which this gene increases stone risk and determine whether it should be a target for future therapeutic and preventative drug development in people.

National Institute of Health (NIH)
Office of The Director, National Institutes of Health (OD)
Research Scientist Development Award - Research & Training (K01)
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Special Emphasis Panel (ZRG1)
Program Officer
Fuchs, Bruce
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University of Minnesota Twin Cities
Veterinary Sciences
Schools of Veterinary Medicine
United States
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Torres, Sheila M F; Furrow, Eva; Souza, Clarissa P et al. (2018) Salivary proteomics of healthy dogs: An in depth catalog. PLoS One 13:e0191307
Landry, Greg M; Furrow, Eva; Holmes, Heather L et al. (2018) Cloning, function, and localization of human, canine and Drosophila Zip10 (Slc39a10), a Zn2+ transporter. Am J Physiol Renal Physiol :
Smit, M M; Ekenstedt, K J; Minor, K M et al. (2018) Prevalence of the AMHR2 mutation in Miniature Schnauzers and genetic investigation of a Belgian Malinois with persistent Müllerian duct syndrome. Reprod Domest Anim 53:371-376
Minor, K M; Letko, A; Becker, D et al. (2018) Canine NAPEPLD-associated models of human myelin disorders. Sci Rep 8:5818
Furrow, E; Lees, G E; Brown, C A et al. (2017) Glomerular Lesions in Proteinuric Miniature Schnauzer Dogs. Vet Pathol 54:484-489
Furrow, Eva; McCue, Molly E; Lulich, Jody P (2017) Urinary metals in a spontaneous canine model of calcium oxalate urolithiasis. PLoS One 12:e0176595
Lenz, J A; Furrow, E; Craig, L E et al. (2017) Histiocytic sarcoma in 14 miniature schnauzers - a new breed predisposition? J Small Anim Pract 58:461-467
Wakayama, J A; Furrow, E; Merkel, L K et al. (2017) A retrospective study of dogs with atypical hypoadrenocorticism: a diagnostic cut-off or continuum? J Small Anim Pract 58:365-371
Kohnken, Rebecca A; Amerman, Hayley; Brown, Cathy A et al. (2017) Glomerular Lipidosis in Dogs. Vet Pathol 54:795-801
Smith, R E; Granick, J L; Stauthammer, C D et al. (2017) Clinical Consequences of Hypertriglyceridemia-Associated Proteinuria in Miniature Schnauzers. J Vet Intern Med 31:1740-1748

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