The Skaggs Institute
for Chemical Biology
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.
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