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The Skaggs Institute
for Chemical Biology


Scientific Report 2008




Training in Molecular and Experimental Medicine

E. Beutler

A strong relationship between the basic sciences of chemistry and biology and clinical medicine is essential for understanding the basic biology of disease and the directed development of therapeutic interventions. This understanding requires specific technical training that provides a perspective encompassing both sides. The Skaggs Institute for Chemical Biology has attempted to provide such training by supporting young scientists in the Department of Molecular and Experimental Medicine.

Christian Nievera, under the supervision of Xiaohua Wu, associate professor, is studying molecular mechanisms involved in the maintenance of genome stability and repair after DNA damage. Genome instability and aberrant DNA repair lead to gross chromosomal rearrangement, a major underlying cause for tumorigenesis. Dr. Nievera is determining the role of the Mre11/Rad50/Nbs1 (MRN) complex and its interaction with replication protein A in modulating the S-phase checkpoint after DNA damage. He is examining the mechanism by which this interaction leads to the suppression of replication origin firing in response to DNA damage. Furthermore, he has found that MRN interacts directly with the breast cancer suppressor protein BRCA1. He is determining how BRCA1 works with MRN to repair DNA. Because much of natural resistance to malignant transformation due to mutational events appears to be related to the capacity of cells to preserve the integrity of DNA, an understanding of the mechanisms involved in these responses is critical.

Jaroslav Truksa, a trainee in my laboratory, has been studying transcriptional regulation of hepcidin, a critical regulator of iron metabolism. Hepcidin appears to be particularly important in anemia of chronic inflammation and iron refractory anemia. Aberrant hepcidin expression is also associated with hemochromatosis. Dr. Truksa has used innovative methods—a luciferase reporter and in vivo bioluminescence—to study transcriptional regulation in intact animals. With this technology, he has defined an upstream region of the hepcidin promoter that is important in the response to ingested iron. Using tissue culture methods, he has defined a second, distinct region in the hepcidin promoter that responds to cytokine stimulation.

In addition, he examined the role of Tmprss6, a novel protein associated with iron refractory anemia in humans, and found that it suppresses the total level of expression of hepcidin induced by inflammatory cytokines and bone morphogenic proteins. Dr. Truksa is also examining the repression of hepcidin by growth differentiation factor GDF15, which is highly expressed in thalassemia. He is investigating the intracellular mediators involved in signaling between the cell-surface modulators of iron (hemojuvelin, HFE, TfR2, and Tmprss6) and the hepcidin gene. Understanding the pathway of iron regulation by hepcidin will provide insight into the future management both primary and secondary iron storage diseases.

Each of the trainees has fulfilled the goals of the Skaggs program by applying basic scientific knowledge and techniques to disease-related biologic systems. They have each published several articles in outstanding journals and have made or are making contributions to the understanding of clinical disorders.

 

Ernest Beutler, M.D. Professor
Chairman, Department of Molecular and Experimental Medicine

Beutler Web Site