Chemistry and
Biochemistry Faculty Projects
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Professor Justin Shearer overseeing student
in chemistry project.
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Characterization of the estrogen receptor ligand-binding
domain
Professor Mark Brandt
The estrogen receptors interact with the "female" sex steroid
hormones to regulate normal growth and development in both genders.
In addition, the estrogen receptors are implicated in the
initiation and growth of several types of tumors, of which breast
cancer is the most common. Binding of ligand to the estrogen
receptor is known to alter the shape of the protein in ways that
alter its function. However, the details of this conformational
change in the protein are incompletely understood. In order to
examine these changes, we express the ligand-binding domain of the
estrogen receptor in bacteria. The bacterial expression allows us
to produce the protein in large quantities, and allows us to
produce modified forms of the protein with novel properties. We
then characterize interactions between the protein and both ligands
and other small molecules. Methods used to probe the effects of
these compounds on the protein structure include HPLC gel
filtration chromatography and fluorescence spectroscopy. Work in
the laboratory thus involves DNA manipulation and other molecular
biological techniques for generating new mutant expression
plasmids, protein purification techniques, and HPLC-based and
fluorescence-based experiments for characterizing the estrogen
receptor protein. In addition, we have been using molecular docking
and molecular dynamics computer simulations to in in analyzing the
experimental results and to help in planning additional
experiments. The overall goal of the project is to understand the
mechanisms by which this important protein has its effects, and
possibly to allow generation of improved treatments for
estrogen-dependent tumors.
New tools to fight drug-resistant breast
cancer
Professor Ross Weatherman
One of the major challenges in treating breast cancer is that
tumor cells eventually develop resistance to the drugs trying to
treat them. My work focuses on synthesizing and testing new
compounds specifically targeted to overcome resistance of breast
cancer cells to tamoxifen, a common drug used to treat estrogen
receptor-positive breast cancer. The projects will focus on the
design and chemical synthesis of new compounds and new delivery
methods, but will also include preclinical testing of compounds
through binding and cell-based experiments. Some knowledge of
organic chemistry is highly suggested.
Testing the full estrogenic signaling capabilities of
potential endocrine disrupting chemicals
Professor Ross Weatherman
A major concern for the public is that there are compounds in
the environment, either man-made or natural, that could be
increasing the risk of the exposed population to hormone-related
disorders such as cancer and diabetes. There are a number of these
"endocrine disruptors" believed to raise the risk of breast cancer,
but full characterization of most of these compounds has not been
performed. This project will use protein and cell-based assays to
better characterize a number of these compounds and try to develop
a more complete picture of the potential risk of these compounds.
Some basic biology and chemistry experience would be useful, but
not essential.
Sustainable Materials Laundry Tag
Professor Rebecca DeVasher
I have often wondered why frequently used materials don't have a
"laundry tag" that includes pertinent information such as
environmental footprint, proper use and disposal, and potential for
reuse and recyclability. I envision this project to begin with
collecting some information on commonly used industrial materials
and conclude with a database that could be turned into a smart
phone app. A student from any discipline can see how the world of
chemistry can inform sustainable practices in industry.
Atlas of protein fold space
Professor Yosi Shibberu (MA)
Professor Mark Brandt (CHEM)
Professor Allen Holder (MA)
Professor David Goulet (MA)
Proteins play a key role in nearly all the biochemical process
of life. A protein sequence (translated from its corresponding gene
sequence in DNA) collapses into a tightly packed, 3D structure
called a fold. We are interested in developing an atlas of all
known protein folds. Such an atlas will aid in identifying the
function of individual proteins and potentially lead to the design
of proteins with new functions. An atlas is built by comparing all
pairs of proteins from a large database. Our pairwise
comparison technique uses eigenvalues and eigenvectors and has
proven to be efficient and accurate on sizable test sets.
Dimerization of the estrogen receptor
protein
Professor Yosi Shibberu (MA)
Professor Mark Brandt (CHEM)
Professor Allen Holder (MA)
Professor David Goulet (MA)
The estrogen receptor protein is the drug target of tamoxifen,
one of the most successful drugs for treating breast cancer. We are
interested in computer simulations of this protein to better
understand how it functions. Some of our simulations have required
more than a month of computation on the mathematics department's
48-core workstation. Each simulation generates several gigabytes of
data to analyze. The project has important implications for both
breast cancer research and for modeling protein-protein and
protein-small molecule interactions.
Probing 8-Hydroxy-2'-Deoxyguanosine as a marker of
oxidative DNA damage
Professor Daniel Morris
Nucleoside derivatives, especially those that are
guanosine-based, are important markers for diagnosing and/or
monitoring serious diseases and clinical conditions. These
markers include several methylated guanosine derivatives associated
with thyroid cancer and the ubiquitous oxidative DNA damage marker
8-hydroxy-2'-deoxyguanosine (8-OH-dG). With the exclusion of
ionizing radiation, oxidative DNA damage is associated with the
metal-dependent decomposition of H2O2 and subsequent generation of
reactive oxygen species (ROS). Oxidative damage to DNA
appears to be very selective with the guanosine-based derivative
8-OH-dG increasing substantially over background levels.
Evidence suggests that DNA has the capability of binding metal
ions, and reaction of H2O2 at or close to the site of metal binding
would account for the selective nature of oxidative damage.
Given the variety of sites in DNA to which metal ions can bind
(phosphate groups vs. different positions on individual bases),
questions arise regarding the relationship between DNA binding
sites and production of modified nucleosides. We study the
interactions of metal ions with the calf thymus DNA (CT-DNA) and
probe the ability of the metal ion/H2O2 systems to produce
8-OH-dG. Our current work focuses on the ability of selenium
compounds to act as both anti- and pro-oxidants for metal ion
mediated oxidative damage. The mechanism by which inorganic
selenium compounds decrease metal ion-mediated oxidative damage is
reported to involve metal ion coordination. We perform experiments
in which the selenium compounds are added to DNA before (Condition
1) and after (Condition 2) the metal ions to determine if the
selenium compounds are limited to coordinating only free metal ions
in solution or if they are capable of competing effectively with
DNA for these metal ions. Understanding the mechanisms behind
the observed antioxidant and pro-oxidant activity of compounds is
an important goal in the treatment and prevention of many diseases
and clinical conditions.
Synthesis and applications of carbon cryogels in
environmental science and separations
Professor Justin W. Shearer
Carbon cryogels are a unique form of carbonaceous media that are
characterized by being greater than 60% porous and containing
micropores and mesopores. There are several projects in which
carbon cryogels are being synthesized and used in separation
science and environmental chemistry:
- The design of uniformly sized carbon microspheres is attractive
in the field of analytical separations. In order to
synthesize carbon microspheres, a mixture of microfabrication and
wet chemistry can be employed. Carbon microspheres can be
used as material to be packed into high-performance liquid
chromatography columns and tested for the quantitative analysis of
many classes of environmental contaminants.
- Monolithic materials are also quite attractive in the field of
separation science, as the diffusion of peaks in a chromatographic
analysis due to mass transport can be minimized. The
synthetic pathway to obtaining carbon cryogels also lends to the
fabrication of carbon monoliths. Carbon monoliths can be used
in chromatographic separations and extraction studies to quantifiy
or remediate environmental contaminants. It is also possible
to perform electrochemical separations with carbon cryogels for
heavy metal clean-up.
- Functional modification of carbon cryogels can also be
accomplished by doping chemical species at specific points during
the synthesis. The ability to modify the functionality of a
separation medium could lead to widespread application of the
material in separations.