Developmental, translational and clinical studies for skeletal disorders and inborn errors of metabolism
As a pediatrician and geneticist, the overall mission of my research program is to translate the study of structural birth defects and inborn errors of metabolism into a basic understanding of development, disease and novel therapeutic approaches. My long standing focus has been the study of human inborn errors of metabolism and structural birth defects of the skeleton. We have applied genetic approaches to the study of biochemical genetic disorders (specifically urea cycle disorders) as models of complex disease (those involving nitric oxide dysregulation). Because of this focus, we have studied metabolic derangements broadly in the endocrine, cardiovascular, skeletal, renal systems.
In the area of structural birth defects, we have studied paracrine and endocrine signaling pathways that regulate skeletal development including morphogens (TGFb, Wnt and Notch), post-transcriptional regulation by microRNAs, and extracellular matrix modifications (collagen prolyl-hydroxylation). These developmental pathways have led me to ask how their dysregulation in postnatal life lead to common diseases such as osteoporosis, osteoarthritis, and cancer.
An emerging area is how these mechanism may also broadly translate into the pathogenesis of heritable disorders of connective tissue. Ultimately, I have attempted to translate these findings by developing cell and helper-dependent adenoviral gene transfer for these conditions. A unifying approach is to identify new genetic basis of skeletal dysplasias (over 15) to inform mechanistic and therapeutic studies. My laboratory research program is linked with clinical research that is performed as part of the Skeletal Dysplasia Clinic and the Metabolic Disorders Clinic at Texas Children’s Hospital, respectively, and two clinical research networks.
My clinical research program began with stable isotopic measurements in humans and urea cycle disorder patients to better diagnose patients with disorders of urea cycle flux and to evaluate the differential bioavailability of different sources of nitrogen (enteral vs. parenteral) to the urea cycle. These human studies have evolved to assessment of nitric oxide flux in patients with UCDs and specifically with argininosuccinic aciduria. I have participated in and led both investigator initiated and industry sponsored interventional studies including the design of Phase II and III studies of a novel ammonia scavenger glyceryl-triphenylbutyrate in urea cycle patients, combinatorial phenylbutyrate/arginine treatment in patients with argininosuccinic aciduria, and zoledronic acid and teriparatide treatment in pediatric and adult osteogenesis imperfecta, respectively.