|
Translational studies of skeletal and kidney development, 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 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 skeletal and kidney development.
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 two transcription factors Runx2 and Lmx1b important in these processes, and how they contribute to
environment-gene interactions that cause craniofacial/limb malformations and to Wnt-signaling pathways during skeletogenesis.
These basic and translational studies are linked intimately with clinical research performed in 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 osteopenia 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. With this already in hand, we have attempted to translate
the basic information into stable isotope based metabolic protocols in urea cycle patients to develop new tools for diagnosis
and clinical management. 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 other biochemical pathways that constitute
key gene-nutrient interactions during postnatal growth and development. The ultimate goal is to translate information from
these well studied pathways into treatment. This is the focus of our gene replacement studies using helper-dependent
adenoviral vectors in urea cycle disorders. An integral 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.
Selected Publications
Dreyer SD, Zhou G, Baldini A, Winterpacht A, Zabel B, Cole W, Johnson RL, Lee B (1998)
Mutations in LMX1B cause abnormal skeletal patterning and renal dysplasia in nail patella syndrome.
Nature Genetics 19:47-50.
Chen H, Lun Y, Ovchinnikov D, Kokubo H, Oberg KC, Pepicelli CV, Gan L, Lee B, Johnson RL (1998)
Limb and kidney defects in Lmx1b mutant mice suggest an involvement of LMX1B in human nail patella
syndrome. Nature Genetics 19:51-55.
Lee B, Dennis JA, Healy PJ, Mull B, Pastore L, Yu H, Aguilar-Cordova E, O'Brien W, Reeds P, Beaudet AL (1999)
Hepatocyte gene therapy in a large animal: a neonatal bovine model of citrullinemia. Proceedings of the National
Academy of Sciences U.S.A. 96:3981-3986.
Lee B, Yu H, Jahoor F, O'Brien W, Beaudet AL, Reeds P (2000) In vivo urea cycle flux distinguishes
and correlates with phenotypic severity in disorders of the urea cycle. Proceedings of the National
Academy of Sciences U.S.A. 97:8021-8026.
Dreyer SD, Morello R, German MS, Zabel B, Winterpacht A, Lunstrum GP, Horton WA, Oberg KC,
Lee B (2000) LMX1B transactivation and expression in nail-patella syndrome. Human Molecular
Genetics 9:1067-1074.
Morello R, Zhou G, Dreyer SD, Harvey SJ, Ninomiya Y, Thorner PS, Miner JH, Cole W, Winterpacht A, Zabel B,
Oberg KC, Lee B (2001) Regulation of glomerular basement membrane collagen expression by LMX1B
contributes to renal disease in nail patella syndrome. Nature Genetics 27:205-208.
Miner JH, Morello R, Andrews KL, Li C, Antignac C, Shaw AS, Lee B (2002) Transcriptional induction of
slit diaphragm genes by Lmx1b is required in podocyte differentiation. Journal of Clinical Investigation
109:1065-1072.
Hamano Y, Grunkemeyer JA, Sudhakar A, Zeisberg M, Cosgrove D, Morello R, Lee B, Sugimoto H, Kalluri R (2002)
Determinants of vascular permeability in the kidney glomerulus. Journal of Biological Chemistry 277:31154-31162.
Zheng Q, Zhou G, Morello R, Chen Y, Garcia-Rojas X, Lee B (2003) Type X collagen gene regulation by
Runx2 contributes directly to its hypertrophic chondrocyte-specific expression in vivo. Journal of Cell Biology
162:833-842.
Contact Information
- Brendan Lee, M.D., Ph.D.
- Department of Molecular and Human Genetics
- Baylor College of Medicine
- One Baylor Plaza 630E
- Houston, Texas 77030, U.S.A.
- Tel: (713) 798-8835
- Fax: (713) 798-5073
- E-mail: blee@bcm.tmc.edu
|
