The role of zinc transporters and dietary zinc in calcium oxalate urolithiasis

University Of Minnesota, Minneapolis MN

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Abstract

? DESCRIPTION (provided by applicant): 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.