|
|
Selecting
a Research Advisor |
Your senior thesis
is not just 'another course', it is the culmination
of your years of study at Hamilton and is supposed
to provide a 'capstone' experience in the
concentration. A successful senior thesis can also
provide an important stepping stone to graduate or
professional school, employment, whatever you
choose to do after Hamilton.
The allocation of
students to thesis advisors is a two-stage process.
First, you should start talking to potential
advisors about their research areas and submit a
ranked list of at least two, preferably three,
faculty with whom you would like to work. Your
ranking should be given to the Chair of the
Biochemistry Program prior to Spring Break. The
faculty will then take your preferences, as well as
the preferences of Biology and Chemistry students,
to allocate students among the available labs. We
try to maximize the number of students getting
their first choice of lab but also have to
distribute students as evenly as possible amongst
the faculty. You will be notified who will be your
senior thesis advisor soon after spring break. You
then need to start working with your advisor to
develop a short proposal describing your research
project which should be submitted to the Program
Chair by May 1st for approval by the Biochemistry
Program Committee.
|
Faculty
Research Projects |
Wei-Jen Chang |
Biochemistry, Bioinformatics
|
Sci Center 2085, x4296 |
|
Tim
Elgren |
Biophysical
Chemistry |
Sci Center 1076, x4695 |
Encapsulation of Enzymes: Novel Catalytic Bio-materials
Research in my lab continues to focus on sol-gel encapsulation of metalloenzymes. We seek to use these optically transparent materials as a novel approach to studying enzyme mechanism. In many instances, the enzyme remains active and hydrated within the pores of the gel. These catalytically active biomaterials have great potential as robust heterogeneous catalysts. The porous nature of the protein:sol-gel material allows diffusion of substrate and product to and from the encapsulated enzyme. Turnover rates in this environment no longer follow standard enzyme saturation kinetics. Instead, the rate of enzyme turnover is governed by mass transport of the substrate (and product) through the porous network. These slow rates have allowed us to investigate intermediates that occur during enzyme turnover. In addition to the mechanistic studies, we are synthesizing sol-gel materials that will better facilitate electron transfer with the encapsulated enzyme.
The research in my laboratory focuses on the
mechanisms of nitrogen uptake and utilization in
the yeast, Saccharomyces cerevisiae, and how these
processes are controlled so that the cells can grow
most efficiently on the available nutrients. My
main approach to this question involves the
analysis of mutants defective in amino acid uptake
and utilization by molecular genetic and
biochemical techniques. I am interested in cloning
the defective genes in these mutants and analyzing
the normal function of their gene products in amino
acid metabolism. Methods I am currently using
include; recombinant DNA technology to clone the
genes, biochemical assays (enzyme levels- e.g.
glutamate dehydrogenase or metabolites e.g.
storage carbohydrates) and fluorescence microscopy
to observe the mutant cells under various growth
conditions. Projects that are primarily genetics,
biochemistry or cell biology are possible in my
lab. Anyone considering a senior project in my lab
must have completed Bio 225, and students who have
completed an upper-level course in molecular
biology (Bio. 336, 446, or 448) would be at a
distinct advantage.
Previous Senior Projects:
1. Tryptophan transport studies in the yeast,
Saccharomyces cerevisiae.
2. Restriction mapping and subcloning of the AAT1
gene from the yeast, Saccharomyces cerevisiae.
3. Accumulation of storage carbohydrates in aat
mutants of Saccharomyces cerevisiae.
4. Glutamate dehydrogenase levels in S. cerevisiae
mutants.
Our research focuses on the broad area of the chemistry of natural products. Currently this consists of three principal parts. First, We are interested in exploring both marine and terrrestrial plants and organisms for compounds of biological significance, primarily with antineoplastic or antibiotic activity. In particular we have a long-standing interest in the sponge Stylotella aurantium, relatively common in the western Pacific. It has afforded a variety of active compounds, most notably palau’amine (1), whose structure was recently revised; it is currently under investigation as a potential drug, and a number of groups throughout the world are pursuing its synthesis. We are actively pursuing other components of the sponge that also are active in our screens as well as studying its well documented base-catalyzed decomposition.
We also have been studying the chemical ecology of a variety of asters that grow in upstate New York and their predators, the larvae of two nymphalid butterflies. Of particular interest is the chirality of germacrene D (2) and how its chiral composition influences settling and herbivory among the asters. In particular, we have found that the chiral composition of the germacrene D varies among the different aster species and also among different members of a particular aster species. Preliminary experiments suggest that the Pearl Crescent favors plants with a high content of the (-) enantiomer. We are working toward testing the preferences by GC-EAD by synthesizing the (+) germacrene D, which is not
readily available in pure form in nature.
A third area involves studying the solution structures of peptides derived from alphafetoprotein (AFP). Secreted by the fetus and circulated in the bloodstream to the mother, AFP has been shown to endow women who have had children with some protection against estrogen-mediated breast cancer. The active portion of AFP appears to be an octameric peptide. Computational chemistry has demonstrated that there are several active small peptides that also are active against breast cancer cells.[1] We have embarked on a program that experimentally studies the solution structures of these peptides to confirm the computational results and to then attempt to synthesize some peptidomimetic compounds that would be potentially useful therapeutically, since the peptides themselves would have short lifetimes in a cancer patient.
1. Kirschner, Karl N.; Lexa, Katrina W.; Salisburg, Amanda M.; Alser, Katherine A.; Joseph, Leroy; Andersen, Thomas T.; Bennett, James A.; Jacobson, Herbert I.; Shields, George C., Computational Design and Experimental Discovery of an Antiestrogenic Peptide Derived from a-Fetoprotein. Journal of the American Chemical Society (2007), 129(19), 6263-6268.
- Fundamental to the proper function of the
nervous system is the highly ordered and
specific expression of neurotransmitters and
neuropeptides. What factors are involved in the
decision to express a specific neurotransmitter
during development? Moreover, neurotransmitter
levels in mature neurons may vary. What factors
are responsible for short-term changes in
neurotransmitter synthesis? Research in my
laboratory focuses on these questions in the
nervous system of an experimentally favorable
insect, Manduca sexta.
I have been examining the development of a
biogenic monoamine, octopamine, in the abdominal
nervous system of Manduca to understand the
developmental mechanisms controlling
neurotransmitter synthesis. Specifically, I am
studying tyramine b-hydroxylase (TbH), the
rate-limiting enzyme controlling octopamine
biosynthesis. TbH has many biochemical
characteristics in common with the mammalian enzyme
dopamine b-hydroxylase. I have discovered that TbH
is developmentally regulated during metamorphosis
and the proper expression of TbH requires the
presence of steroid hormones. Other studies are
directed towards understanding the molecular basis
of steroid regulation of TbH, the physiological
role of octopaminergic neurons in the abdominal
nervous system, and short-term control of TbH
activity.
Another long-standing research interest in my
laboratory is the structure and function of
neuropeptides. I have been isolating and sequencing
novel neuropeptides from the nervous systems of
several invertebrates using bioassays and
immunological techniques. My ultimate goal is to
compare and contrast long- and short-term
regulatory mechanisms of biogenic amines and
neuropeptides.
A person considering a senior project in my lab
must have completed Bio 225 and an upper-level
course in cellular, molecular, or neurobiology (Bio
330, Bio 336, or Bio 446) is strongly
recommended.
Formation, structure and reactivity of biogenic minerals; biological transformation of contaminants by metal-reducing bacteria; characterization of the cell / mineral interface
The research in my laboratory focuses on the use
of computational chemistry to understand biological
processes. We use both quantum chemistry and
molecular dynamics simulations to model reactions,
with special consideration given to the role of
solvent in these simulations. One project involving
quantum chemistry focuses on fundamental
understanding of the way antibodies recognize and
"trap" antigens. We are interested in discovering a
molecule that looks like a transition state for the
hydrolysis of cocaine. Such a molecule, known as a
transition state analog, when injected into a mouse
will elicit antibodies. Some of the antibodies will
act as catalysts for the reaction of interest.1 We
are working with a collaborator at Columbia Medical
School as we try to learn how to use quantum
chemistry in conjunction with experiments to
develop catalytic antibodies.2-4 Another project
involving molecular dynamics simulations focuses on
fundamental understanding of how DNA interacts with
small drug molecules. In one approach, we have
modeled triple-stranded DNA helices, an approach
that has much interest in the pharmaceutical
industry because of the potential to design drugs
that are gene-specific.5,6 We are continuing these
types of simulations, including the use of small
molecules which attach to the minor groove and
stabilize the DNA double helix. These, and other
projects, all require an ability to read and
understand the experimental literature combined
with the motivation to learn how to perform
simulations and to learn from the results. From a
student's perspective, running computer simulations
are similar in process to performing experiments:
you run the simulation until you get it to work,
you analyze the results, think about what has
happened, and then plan the next simulation.
References
1. Science 234 1566-70 (1986)
2. Science 259 1899-1901 (1993)
3. J. Phys. Chem. A 101 8526-29 (1997)
4. J. Mol. Model. 2 62-69 (1996)
5. J. Am. Chem. Soc. 119 7463-69 (1997)
6. J. Am. Chem. Soc. 120 5895-5904 (1998)
Project 1: Exploring the Nature of Ligand Binding in the Active Site of Galectin-1 Using Natural and Unnatural Carbohydrates
Galectin-1 is a protein that has been implicated in a number of biological events including tumor progression, inflammation and immunity, and HIV infectivity. Ligands that selectively target galectin-1 have the potential to serve as effective treatments for cancer, certain inflammatory diseases, and the Human Immunodeficiency Virus. Despite recent advances in the preparation and evaluation of a host of ligands that target and bind galectin-1, little is known about the nature of the galectin-1-ligand binding interaction. Research in our lab focuses on the design, preparation, and biological assessment of a number of lactosyl triazoles that mimic the natural ligand of galectin-1. These derivatives will be used to further an understanding of galectin-1-ligand binding interactions. The results obtained through these studies will serve as a foundation for the design and preparation of agents that selectively target galectin-1.
Project 2: The Synthesis and Biological Evaluation of a Vancomycin Derivative Incorporating an Unnatural Carbohydrate at the Vancosamine Position
Vancomycin is a broad spectrum antibiotic that is generally used as a “last resort” for the treatment of gram positive bacterialinfections, such as those caused by staphylococcus. Vancomycin is composed of two bioactive components, a cyclic peptide component (aglycon) and a functionalized carbohydrate component (glycan), that work synergistically through a mechanism that is not well understood, to blocking the approach of several key enzymes involved in bacteria cell wall biosynthesis. Over the past twenty years, several vancomycin-resistant strains of bacteria have emerged. This has led researchers to search for new and more potent derivatives of vancomycin. Most of this research has focused on making improvements to the aglycon. Researchers in my group are currently focused on the preparation of a new derivative of vancomycin that incorporates an unnatural carbohydrate residue at a key position of the glycan. The derivative currently under investigation will be used to provide a better understanding of the role of the carbohydrate component in the inhibition of bacteria cell wall biosynthesis. The results of these studies will ultimately be used to design a vancomycin derivative that can be used to treat resistant strains of gram positive bacteria.
Project 3: Exploring Platinum Anti-tumor Chemistry Using Carbohydrate-Based Enediyne Cisplatin Conjugates
Cisplatin, an effective anti-tumor agent, has been used to treat a number of different types of cancer. Unfortunately, severe toxic side effects and the emergence of resistant tumor cell lines have limited or prohibited the use of this drug in certain patients. This has prompted researchers to search for improved derivatives of cisplatin. Ongoing research in my laboratory focuses on the synthesis, characterization, and biological evaluation of an entirely new class of cisplatin derivatives that have the potential to reduce unwanted side effects and treat cisplatin resistant tumor strains. The derivatives we are preparing are novel in that they are the first examples of cisplatin derivatives to incorporate a carbohydrate-based enediyne group. The knowledge gained through the synthesis and biological evaluation of these derivatives will serve to further a general understanding of the anti-tumor properties of cisplatin analogs. Long term objectives for this project will focus the design and synthesis of cisplatin analogs that will be used to target specific cancer types.
|
|
