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Abstract
Glutathione is a ubiquitous antioxidant with roles in xenobiotic clearance, free radical neutralization, and other physiological functions. Glutathione exists in a balance between its reduced and oxidized forms, GSH and GSSG, respectively, to participate in oxidation-reduction (redox) reactions. The intracellular concentrations of GSH are tightly controlled to ensure precise balance of redox homeostasis. When GSH metabolism is altered, oxidative stress can arise and result in deleterious consequences that have been associated with many chronic diseases. Traditional methods to understand the genetic basis of the GSH antioxidant system were confined to canonical GSH genes using inbred mouse strains, affording limited translatability to human populations. Recently, evidence has suggested that novel genes may influence GSH metabolism in a tissue-specific manner, but little is known about GSH regulation in the cardiovascular and cortical systems. In addition, the development of population biobanks has made it possible to explore the health impact of murine candidate genes in human populations. Growth differentiation factor-11 (GDF11) is a circulating protein that has been implicated in GSH regulation indirectly through its involvement in antioxidant signaling, and evidence from mouse models suggests that GDF11 functions as an anti-aging factor. Yet, the impact of GDF11 variation in human populations remains unclear. Therefore, the objective of this dissertation was to define the genetic architecture of the vital GSH antioxidant system in the heart and cerebral cortex of genetically diverse mice and to explore the health impact of GDF11 variation in human populations. Chapter 3 details the results from high-precision genetic mapping of GSH phenotypes in the cardiovascular system of a large cohort of genetically diverse mice. Chapter 4 explores variation in the cortical GSH redox system and constructs a comprehensive model of GSH status among major tissues. Lastly, Chapter 5 reveals novel associations between GDF11 and health from genome-wide association study (GWAS) results housed in population biobanks. Overall, the studies of this dissertation will expand our current knowledge of how genetics drive variation in the vital glutathione antioxidant system and its impact on human health and will ultimately contribute to the development of clinical therapeutics and personalized medicine.