Kenneth Setchell, PhD
For more than 30 years, Cincinnati Children's has implemented an international screening diagnostic program for underlying genetic metabolic disorders of cholestatic liver disease. As a result of the decades of work by Dr. Ken Setchell, this program has come full circle from the original recognition of the metabolic defects to establishing a diagnostic laboratory analysis to identify these disorders and now a highly effective treatment program based on these many years of work. This is a result of Dr. Setchell’s research investigations using mass spectrometry that he identified at least six genetic defects in bile acid synthesis. These conditions are fatal if not treated in these patients. After Dr. Setchell began to recognize and identify these unique genetic defects in these patients, he then established a highly successful diagnostic laboratory service based on mass spectrometry and is now still the world’s reference lab for the identification of these underlying metabolic defects in bile acid synthesis. Dr. Setchell’s lab receives clinical specimens from patients all around the world including China, Middle East, Europe, South America, and the United State. In recognition of his significant contributions to these unique disorders of liver disease in children, he was recently invited as the plenary speaker at the American Association of Clinical Chemists to describe the history, successful diagnostic testing development and, now successful therapeutic drug program based on his efforts in collaboration with Dr. James Heubi, which is FDA approved for the management of these patients. This dramatic success, based on the work of Dr. Setchell and his colleagues, is a testament to the talent and hard work of many investigators here at Cincinnati Children's.
Gang Huang, PhD
Dr. Gang Huang and his collaborators at Cincinnati Children's may be on the road to solving the mystery of a mostly incurable blood disease called myelodysplastic syndrome (MDS), which causes people to have immature, malfunctioning bone marrow cells that fuel a diverse set of health problems and can lead to leukemia. The incidence is increasing with global population ageing. Although many genetic, epigenetic, splicing, and metabolic aberrations have been identified in MDS patients, their clinical features are quite similar. There studies show that hypoxia-independent activation of hypoxia-inducible factor 1α (HIF1A) signaling is both necessary and sufficient to induce dysplastic and cytopenic MDS phenotypes. The HIF1A transcriptional signature is generally activated in MDS-patient bone-marrow stem/progenitorsMajor MDS-associated mutations (Dnmt3a, Tet2, Asxl1, Runx1, and Mll1) activate the HIF1A signature. While inducible activation of HIF1A signaling in hematopoietic cells is sufficient to induce MDS phenotypes, both genetic and chemical inhibition of HIF1A signaling rescues MDS phenotypes in a mouse model of MDS. These findings reveal HIF1A as a central pathobiologic mediator of MDS, and as an effective therapeutic target for a broad spectrum of MDS patients.
