The Skaggs Institute
for Chemical Biology
Training in Molecular and Experimental Medicine
Exploring the experimental interface between the basic sciences of chemistry, biology, and
clinical medicine requires specific technical training in a context that also provides
a perspective encompassing both sides of the interface, if the exploration is to
be more than just examining compounds for their activity in disease models. The
Skaggs Institute for Chemical Biology has attempted to develop such explorers by
supporting young scientists in the Department of Molecular and Experimental Medicine
at Scripps Research.
Nievera, under the tutelage of Xiaohua Wu, assistant professor in the Division of
Molecular Oncology, is studying molecular mechanisms involved in cell-cycle arrest
in response to DNA damage. 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 whether the MRN complex directly inhibits
DNA replication as well as being involved in transducing DNA damage signals. Because
much of the natural resistance to malignant transformation due to mutational events
appears to be related to the cells' capacity to preserve the integrity of DNA,
an understanding of the mechanisms involved in these responses is critical.
Lee, also working in Dr. Wu's group, has focused on the role of MRN in preventing
re-replication of DNA after Cdt1 overexpression. Loss of the complex increases re-replication
in susceptible cell lines but also leads to re-replication in cells normally resistant
to the process. MRN apparently works by facilitating activation of the ataxia telangiectasiamutated
and Rad3-related (ATR) pathway to phosphorylate Chk1. The Nbs1 component of the
MRN complex is also a substrate of ATR, and its phosphorylation at S343 by ATR occurs
early after Cdt1 is overexpressed. The failure to phosphorylate leads to more aggressive
re-replication. These studies draw attention to the critical role of the intact
MRN complex in the process.
a trainee in my laboratory in the Division of Hematology and Genetics, has been
studying transcriptional regulation of hepcidin, a critical regulator of iron metabolism.
Hepcidin appears to be particularly important in the anemia of chronic inflammation,
one of the most common forms of anemia, and understanding of the function of hepcidin
is also likely to provide insight into iron storage diseases. 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 same promoter that responds to cytokine stimulation.
is receiving his postdoctoral training from Professor Joel Buxbaum, head of the
Division of Rheumatology Research. In studies on the physiologic role of the serum
and cerebrospinal fluid protein transthyretin, Dr. Ye noted that a number of published
reports suggested that cerebral transcription of the gene encoding the protein was
increased in several neurodegenerative disorders, most prominently Alzheimer's
disease. Using surface plasmon resonance, he showed that both murine and human transthyretin
bound aggregates of the Alzheimer-associated amyloid β1–40
and amyloid β1–42
peptides but did not bind the peptide monomers. These data provided a mechanistic
explanation of in vivo experiments in the Buxbaum laboratory, showing that overexpression
of human transthyretin in a murine model of Alzheimer's disease suppressed
the neuropathologic, behavioral, and biochemical phenotype; the same model had an
accelerated course in mice in which the endogenous transthyretin had been silenced
by targeted disruption.
Each of the
trainees has fulfilled the goals of the Skaggs program by applying basic science
knowledge and techniques to disease-related biologic systems. They have made or
are making contributions to the understanding of the clinical disorders.