The Skaggs Institute
for Chemical Biology
Training in Molecular and Experimental Medicine
There has been
widespread national concern about the fact that discoveries in the laboratory are
translated to clinical practice slowly, if at all. The main cause of delay is a
regulatory network that impedes translation, but even if this problem were overcome,
we need a cadre of young scientists trained in the study of human disease, the mechanisms
that underlie the diseases, and their treatment. The Skaggs Institute for Chemical
Biology is helping to achieve this goal by supporting the training of young scientists
in the Department of Molecular and Experimental Medicine at Scripps Research.
Lee is studying the mechanisms by which the S-phase checkpoint is operated in mammalian
cells. Genome instability is a hallmark of the malignant phenotype and a driving
force for tumorigenesis. The S-phase checkpoint is a principal defense mechanism
to maintain genome stability. Mutations in checkpoint genes contribute to many types
of lymphoid malignant neoplasms, particularly in the context of ataxia telangiectasia,
which has a defect in the gene for ATM and impairs the S-phase checkpoint.
The detailed mechanism by which the S-phase
checkpoint is operated in mammalian cells remains unclear. Dr. Lees preliminary
data suggest an important role for the regulatory subunit Dbf4 of the kinase Cdc7.
The phosphorylation modification of Dbf4 in response to DNA damage and the mechanism
by which Dbf4/Cdc7 participates in the S-phase checkpoint will be investigated.
These studies may clarify molecular pathways that link damage signal transduction
through Dbf4/Cdc7 to the effector proteins to regulate the S-phase checkpoint.
They will help to elucidate the overall mechanism of the S-phase checkpoint in mammalian
cells and shed light on the cellular mechanisms that control genome stability and
Jaroslav Truksa is studying the regulation
of the transcription of hepcidin, an antimicrobial peptide that plays a key role
in iron metabolism. He is investigating the molecular mechanisms that lead to hepcidin
upregulation after stimulation with IL-6, bone morphogenetic protein 9, or iron.
He has developed a luciferase reporter system suitable for use in both cell culture
systems and in vivo imaging, footprinting, and electrophoretic mobility shift assays
to disclose the pathways that regulate hepcidin expression. Better understanding
of hepcidin regulation could provide new drug targets that could be useful in treatment
of patients with anemia of chronic disease and patients with hemochromatosis.
Zhengyi Ye is studying transthyretin
amyloid. Most transthyretin is synthesized in the liver and choroid plexus and secreted
into the blood stream and cerebrospinal fluid. The main function of transthyretin
is to transport thyroid hormone and retinal binding proteinvitamin A complex.
Low levels of transthyretin in the cerebrospinal fluid are common among patients
who have Alzheimers disease. Amyloid beta (Aβ)
peptides in human brain are the pathologic hallmark of Alzheimers disease,
and some in vitro studies suggest that transthyretin interacts with Aβ
and prevents the fibril formation. In a mouse model of Alzheimers disease,
transthyretin was upregulated in the brain, a finding that may account for the less
severe phenotypes in the mouse model compared with human patients. One of Dr. Yes
projects is to further study the interaction between Aβ
and transthyretin by using surface plasmon resonance. His data suggest that recombinant
human transthyretin only interacts with the Aβ
fibril and that transthyretin aggregates and monomer have much higher interaction
fibril than tetramer does. Mouse tetramer transthyretin also binds to Aβ
fibril with much higher affinity than human tetramer transthyretin does. He is addressing
the question of whether the binding of transthyretin to the Aβ
fibril prevents the cytotoxic effects of the fibril. He will be working on transthyretin
expression in patients with Alzheimers disease by using real-time polymerase
Wei Zhang is studying the action of pleiotrophin, a secreted, highly conserved cytokine. Pleiotrophin has recently been found to be
an angiogenic factor when applied directly to ischemic myocardium and when expressed
by cancer cells. The mechanisms through which pleiotrophin signals are of major
importance. Pleiotrophin signals through its receptor, receptor protein tyrosine phosphatase (RPTP) β/ζ. The interaction of RPTPβ/ζ with pleiotrophin inactivates the intrinsic tyrosine phosphatase activity of RPTPβ/ζ.
β-Catenin, β-adducin, and Fyn are substrates of RPTPβ/ζ, and the tyrosine phosphorylation levels of these proteins are decreased through
pleiotrophin signaling. Dr. Zhang has found that anaplastic lymphoma kinase is also a substrate of RPTPβ/ζ and is activated by pleiotrophin. Anaplastic lymphoma kinase is not a direct receptor
of pleiotrophin but interacts with and is dephosphorylated by RPTPβ/ζ. He also found that, on the contrary, the kinase activity of Fyn is decreased by
pleiotrophin stimulation. By using an established MCF-7/EGFR-RPTPβ/ζ chimera receptor cell line, more experiments will be conducted to define the mechanisms
through which pleiotrophin-RPTPβ/ζ signaling regulates different cell functions such as proliferation, differentiation,
and angiogenesis through the aforementioned substrates.