Graduation Date

5-2015

Document Type

Master's Thesis

Degree Name

Master of Science

Department or Program

Biological Sciences

Department or Program Chair

Maggie Louie, Ph.D.

First Reader

Pankaj Kapahi, Ph.D.

Second Reader

James Cunningham, Ph.D.

Abstract

Cystinuria is an autosomal recessive disorder characterized by a defective renal transporter involved in the reabsorption of cystine and other dibasic amino acids. This leads to an accumulation of cystine in the urine, resulting in cystine stones. The SLC3A1/SLC7A9 cystine transporter accounts for 90% of cystine reabsorption and mutations in this transporter result in the formation of cystine stones. For this study, micro-computed tomography (µCT) scanning was evaluated for its feasibility to track accurate volumetric measurements of in vivo cystine stone growth in the Slc3a1-/- cystinuric mouse model. Six pharmacological interventions – sulforaphane, methyl selenocysteine, homocysteine, tiopronin, TPEN and a zinc-supplemented diet– were also examined for their efficacy in reducing the rate of cystine stone growth. µCT analysis revealed stone growth proceeds linearly. Sulforaphane and TPEN supplementation resulted in a reduced rate of stone growth when compared to the respective vehicle controls; however, methyl selenocysteine and the zinc-supplemented diet displayed no effect on the rate or nature of stone formation. Homocysteine and tiopronin were shown to worsen stone growth rate. Sulforaphane and TPEN were effective interventions and our findings support both as a potential therapy for a cystinuric mouse model. A combination of treatments targeting the rate of cystine stone formation through similar agents appears to be a novel approach in further understanding cystine stone growth. Therapies that can manage the balance between these agents and adverse side effects provide an avenue to effectively treating cystinuria.

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