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Genetic and Clinical Studies in Skeletal Dysplasias and Inborn Errors of Metabolism

Research Summary

Brendan Lee is interested in the consequences of gene mutations on skeletal development. To understand these consequences, he combines studies on mammalian tissue and organ development with clinical research in patients with skeletal malformations. He is also investigating gene-nutrient interactions and gene therapy in patients who have disorders in the urea cycle, which can lead to brain damage and death.

My goal is to elucidate basic developmental and biochemical pathways that regulate mammalian organogenesis and homeostasis, and to apply this knowledge 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.

Our current studies are focused on the transcription factors Runx2Trps1Sox9, and Lmx1b, and how they contribute to TGFβ (transforming growth factor β) 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 quantifying and treating osteoporosis associated with skeletal dysplasias.

Figure 1: An embryonic mouse kidney section...

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. 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. With 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 focus of our gene replacement studies using helper-dependent adenoviral vectors is development of new treatments. An important component of this is work aimed at understanding and preventing the host innate immune response and acute toxicity associated with adenovirus treatment, as well as the host immune response to the therapeutic protein. My research program extends from gene identification in human disease to correlation of disease mechanisms with normal biological processes and measurement and manipulation of these pathways for diagnosis and treatment in humans and in animal models.

As of May 30, 2012