All ETDs from UAB

Advisory Committee Chair

James A Mobley

Advisory Committee Members

Shannon Bailey

Chad Petit

Natalia Kedishvili

Document Type

Dissertation

Date of Award

2019

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Primary Hyperoxaluria (PH) is a family of three inborn errors of glyoxylate metabolism resulting in endogenous oxalate overproduction. PH1 is the most common and most severe form of the disorder when compared to PH2 and PH3. PH1 can result in systemic oxalosis or end stage renal disease, and there is currently no cure for this disorder. The only curative treatment is combined liver/kidney transplant. The difficulty in defining a cure for the disorder arises from poor knowledge of the sources of endogenous oxalate and a lack of understanding in the underlying pathophysiology of the disorder. For these reasons, we have focused on two approaches to investigate the gaps in knowledge of this disorder. The first, involved targeting the hydroxyproline metabolic pathway, a known source of oxalate, as a therapeutic option for limiting endogenous oxalate production. To investigate this pathway, we developed a hydroxyproline dehydrogenase (HYPDH) KO mouse, along with CHO.HYPDH liver derived cell lines that we have characterized in respect to responses to hydroxyproline exposure. Second, we performed a global proteomics study on PH1 mouse model liver to investigate the underlying pathophysiology of PH1, which is characterized by a loss of activity mutation of alanine: glyoxylate aminotransferase (Agxt). A rigorous study on the effects on absence of Agxt in the liver had previously not yet been performed. The liver is not classically considered an organ of interest in PH1 as there is no phenotypic difference between a PH1 liver and a healthy liver. However, in contrast, we observed significant differences in the Agxt liver proteome including a subtle perturbation in the redox proteome supported by transcriptomic data and GSH measurements. A global proteomics approach combined with more traditional oxidative stress methods revealed previously unappreciated chronic, low level oxidative stress in the PH1 mouse that either method alone would have missed. These findings represent new options for therapeutic treatment of PH1 that could increase the quality of life for PH1 patients.

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