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Brendan H.L. Lee, MD, PhD
Skeletal Dysplasias, Inborn Errors of Metabolism, Urea Cycle Disorders.
Genetic pathways that specify development and homeostasis: Translational studies of skeletal development and urea cycle disorders, and therapy for metabolic diseases
The overall mission of my research program is to elucidate basic developmental and biochemical pathways that regulate mammalian organogenesis and homeostasis, and to apply this to the development of new diagnostic and therapeutic tools for disorders resulting from the dysregulation of these pathways. A common theme is an approach involving the flow of information from the study of human genetic disease phenotypes, to the generation and testing of hypotheses in cell and animal models, to the evaluation of the consequences of these dysregulated processes back in humans, and finally, to the development of treatment protocols. We have focused on elucidating the transcriptional networks governing development and the signaling pathways that regulate them. We correlate human genetic disease phenotypes with mouse models to ask what genes are regulated by and targets of key transcription factors during chondrogenesis, osteoblastogenesis, and limb and kidney formation. Current studies are focused on the transcription factors Runx2, Trps1, Sox9, and Lmx1b, to Tgf? and Notch signaling pathways during skeletogenesis, and novel post-translational modifications of matrix proteins. These basic and translational studies are linked intimately with clinical research performed at the Texas Children's Hospital Skeletal Dysplasia Clinic. Here, the multidisciplinary care of pediatric patients with skeletal malformations is closely linked with studies aimed at understanding the consequences of genetic mutations, and at quantitation and treatment of osteoporosis associated with skeletal dysplasias.
In contrast to developmental pathways, much basic information is already available in well studied biochemical pathways that are critical for homeostasis, such as the urea cycle. Here, we have translated this basic information into stable isotope based metabolic protocols to develop new tools for diagnosis and clinical management of urea cycle patients. By using this unique human disease model and physiologic tools that measure the in vivo activity of this pathway, we are asking questions about the interaction of the urea cycle and the nitric oxide pathways that contribute to key gene-nutrient interactions during postnatal growth and development. The ultimate goal is to develop new treatments and this is the focus of our gene replacement studies using helper-dependent adenoviral vectors. An important component of this is work focused on understanding and preventing the host innate immune response and acute toxicity associated with adenovirus treatment. The spectrum of my research program extends from gene identification in human disease, to correlating mechanisms of disease with normal biological processes, to measuring and manipulating these pathways for diagnosis and treatment in humans and in animal models.
Erez A, Nagamani SC, Shchelochkov OA, Premkumar MH, Campeau PM, Chen Y, Garg HK, Li L, Mian A, Bertin TK, Black JO, Zeng H, Tang Y, Reddy AK, Summar M, O'Brien WE, Harrison DG, Mitch WE, Marini JC, Aschner JL, Bryan NS, Lee B (2011). Requirement of argininosuccinate lyase for systemic nitric oxide production. Nature Medicine 17(12): 1619-26. [Pub Med]
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