Lindsay C. Burrage, MD, PhD
As a physician-scientist and clinical biochemical geneticist, I have a long-standing interest in the pathophysiology of inborn errors of metabolism and their utility as models for more common disorders. Our group uses laboratory-based approaches in murine models and clinical studies to gain greater understanding of the etiology of long-term complications of inborn errors of metabolism with a special focus on urea cycle disorders in order to optimize management strategies for our patients.
One main focus of my research program is to gain a greater understanding of chronic liver disease in individuals with urea cycle disorders. As an investigator in the Urea Cycle Disorders Consortium (UCDC) of the Rare Diseases Clinical Research Network, we used data from the UCDC Longitudinal Study of Urea Cycle Disorders to investigate liver disease in urea cycle disorders. Through this work, we demonstrated an increased prevalence of chronic hepatocellular injury in two distal urea cycle disorders (argininosuccinate lyase deficiency and arginase deficiency) compared to disorders impacting enzymes that are more proximal in the cycle. To follow-up this work, we are performing a more comprehensive assessment of liver disease using serum biomarkers and novel imaging techniques in individuals with urea cycle disorders.
Our clinical study of hepatic complications complements our laboratory-based work in the murine model of argininosuccinate lyase deficiency (ASLD). We are using an ASL-deficient mouse model to investigate mechanisms underlying the chronic hepatic complications observed in our patients. The ASL-deficient mice model the human disorder with urea cycle dysfunction, nitric oxide (NO) deficiency, and chronic hepatocellular injury with hepatomegaly. In addition, as in human patients with the disorder, we have discovered hepatic glycogen accumulation and impaired hepatic glycogenolysis in these mice. We are currently dissecting the relative contributions of urea cycle dysfunction and NO deficiency to chronic hepatocellular injury and hepatic glycogen accumulation in ASL-deficient mice. We are also exploring molecular and biochemical mechanisms by which ASL deficiency causes chronic liver disease.
To complement my independent research program, I am involved in a variety of large interdisciplinary research teams investigating rare and undiagnosed diseases. Locally, at BCM, I have a leadership role in the sequence analysis team (e.g. exome and genome) for the Baylor College of Medicine site for the Undiagnosed Diseases Network (UDN). The work of our team has led to discovery of multiple new disease genes and phenotypic expansion in the setting of a wide variety of phenotypes. In addition, I lead the clinical section of the new BCM Center for Precision Medicine Models. This large collaborative project focuses on the generation and use of precision medicine models to support gene discovery in rare undiagnosed diseases and to facilitate pre-clinical studies to investigate therapies for these disorders.
- Impaired Glycogen Metabolism and Chronic Liver Disease in Urea Cycle Disorders
- Burroughs Wellcome Fund Career Award for Medical Scientists
- Dissecting the Link Between Ureagenesis and Hepatic Glycogen Metabolism
- NIH R01DK126786
Burrage LC, Jain M, Gandolfo L, Lee BH, Members of the Urea Cycle Disorders Consortium, Nagamani SC. (2014). Sodium Phenylbutyrate Decreases Plasma Branched-Chain Amino Acids in Patients with Urea Cycle Disorders. Molecular Genetics and Metabolism 113:131-5.
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