Biomedical Summer Undergraduate Research Experience Program
(B-SURE)
The University of Texas Health Science Center at San Antonio (UTHSCSA)
GACZYNSKA,
Maria (Molecular Medicine): The laboratory
is committed to study the mechanism of biomacromolecular assembles with
the special emphasis on giant proteases to better understand their role
in cancer and aging. To achieve this goal, we blend in our research
a unique array of methods from the crossroads of biophysics, enzymology,
organic chemistry, cell biology and molecular biology. In particular, we
are devoted to study the proteasome, a multifunctional macromolecular assembly
essential in cell cycle progression, signal transduction pathways, immune
response and general "housekeeping" in the human cell. The proteasome is
currently in the center of attention of clinicians and pharmacologists
as a surprisingly promising drug target against multiple myeloma and other
types of cancer. The mechanism of action of proteasome inhibitors as anti-cancer
drugs is poorly understood, which impedes their truly efficient utilization
to battle the disease. One of our goals is to provide an insight
into the differences between structure and function of proteasomes in normal
and neoplastically transformed cells and in cells in aging tissues. We
propose that proteasome, together with other proteases that take a part
in the controlled degradation of regulatory proteins in the cell, constitute
a functional entity. They form multibranched degradation pathways enabling
a tight control of this irreversible process. We postulate that this web
of interactions is dysfunctional in cancer or in aged organisms, creating
a "proteolytic instability". Dissecting the web of interaction and
aiming at its most vulnerable points would enable to manipulate the activities
of the involved proteases to specifically kill tumor cells or to improve
an immune response in aging tissue. Another important player among
the big proteases is the multicorn, a giant multifunctional enzyme discovered
and currently characterized in our laboratory. The multicorn has
a postulated role in cell cycle regulation and participates in the "proteolytic
instability" we observe in cancer and aging. To better understand
"the proteolytic instability" on the cellular level, we are also dissecting
the molecular mechanisms of regulation of activity of the proteasome and
the multicorn. For this purpose, we developed a model of allosteric regulation
of performance of the proteasome. In a small-scale rational drug
design fashion, we created a series small-molecule compounds affecting
the proteasomal activities. Our goal is that the compounds or their
derivatives will become specific and precise drugs against cancer, autoimmune
diseases, stroke and other pathological conditions. Among many methods
and approaches used in my laboratory the most unique is atomic force microscopy
(AFM), an exceptional technique to study dynamics of biomacromolecules
and their interactions with ligands under native conditions. We are
employing AFM to study the giant proteases and, in numerous collaborative
efforts, to investigate DNA-binding proteins, like ORC (origin recognition
complex), MCM (minichromosome maintenance) and helicases, or to examine
a structure of drug-treated DNA.
Students who
work in the lab learn a full array of protein biochemistry and enzymology
methods, atomic force microscopy and spectrofluorometry, as well as standard
molecular biology methods, yeast genetics and mammalian tissue culture
techniques. It is worth to mention that research performed by undergraduate
students in my laboratory was acknowledged in several posters on national
meetings. One paper is currently in press in an undergraduate research
journal (UT Austin), and a paper was published by a summer student
in an undergraduate research journal (UT Austin).
Maria
Gaczynska's Research Web Page.