The proposed project is a five year mentored training experience designed to prepare the applicant for a career in clinically-related basic science research. The candidate has an M.D. and Ph.D. and has research experience in mouse and human studies. The applicant is board-certified in pediatrics and medical genetics and is an Assistant Professor in the Department of Molecular and Human Genetics at Baylor College of Medicine (BCM). The Department of Molecular and Human Genetics at BCM has a long track record of training highly successful translational researchers, and BCM provides a world-class clinical and research training environment. The mentor is a leading expert in the field of inborn errors of metabolism and urea cycle disorders. The advisory committee was selected to complement the mentor's expertise and to provide valuable research and career guidance for the applicant. The career development plan includes participation in seminars, journal clubs, lab meetings, courses, national conferences, career development coursework, monthly mentor meetings, and advisory committee meetings. This research application investigates the etiology of reduced respiratory capacity which has recently been discovered in fibroblasts deficient in argininosuccinate lyase (ASL). Urea cycle disorders, such as argininosuccinate lyase deficiency (ASLD), are among the most common inborn errors of liver metabolism. With early diagnosis and treatment, patients with ASLD are surviving into adulthood but with long-term complications. As a result, new strategies for managing these complications, such as liver dysfunction, must be developed. Because many long-term complications are independent of hyperammonemia, other metabolic mechanisms must explain them. Given that ASL links the urea cycle and citric acid cycle (CAC) and has a structural role in channeling arginine for nitric oxide (NO) production, CAC dysfunction or NO deficiency may explain the energy dysfunction in this disorder. Studies in human and mouse fibroblasts will test whether this energy dysfunction is secondary to electron transport chain or CAC dysfunction and whether this energy dysfunction is due to the structural role of ASL in NO production or to the enzymatic role of ASL in fumarate and arginine production. Because mitochondrial abnormalities are observed in the liver of ASL-deficient humans and mice, energy dysfunction is hypothesized to contribute to this phenotype. ASL-deficient mice will be treated with sodium nitrite or citrate to test whether supplementation with NO or a CAC intermediate will result in improvement in hepatic dysfunction. In addition, this application will leverage an existing human clinical trial investigating whether NO supplementation improves vascular reactivity and neurocognitive function in patients with ASLD to test whether NO supplementation results in improvement in markers of liver dysfunction. This application, which provides a broad research experience in cell studies together with mouse and human studies, and the proposed career development plan will prepare this applicant for a career as an independent research scientist investigating inborn errors of liver metabolism.
Urea cycle disorders, such as argininosuccinate lyase deficiency, are disorders of amino acid metabolism. The proposed project will investigate energy metabolism in this disorder and will test whether supplements that target energy metabolism (e.g. nitric oxide and citrate) will result in improvement in liver dysfunction, one long- term complication of this disorder.
