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Jeffrey M. Becker, Ph.D. Professor Microbiology and of Biochemistry, Cellular,
& Molecular Biology Director, UT-ORNL Graduate Program in Genome Science
& Technology Ph.D., 1970, |
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Major
Research Interests:
The research carried out in our laboratory emphasizes the structure and function of peptide pheromones/hormones and their receptors, the molecular biology of membrane transport, and the discovery of fungal virulence factors and antifungal drugs.
Structure and Function of Peptides
and Peptide Hormone Receptors
We are studying the mating system of Saccharomyces
cerevisiae as a model system of peptide hormone/pheromone biology. Hormones
play a vital role in the regulation of cellular activity. An understanding
of the interaction between a hormone and its receptor is necessary for
comprehending signal transduction/intercellular communication and for
designing analogs useful in therapy of many human disorders. Our
experimental system combines synthetic chemistry, biochemistry, genetics,
molecular biology, and cell biology. We have synthesized and analyzed
analogs of the yeast mating pheromones,
α-factor and a-factor, by a variety of techniques combining
both chemistry and molecular biology. Our studies indicate that a preferred
conformation of the small peptides is necessary for full biological
activity. These new analogs provide useful tools to study ligand-receptor
interactions at the molecular level. We are studying the structure of the
pheromone binding site within the receptor in order to understand how the
pheromone activates the signal transduction pathway after binding to this
site. These experiments are performed on a battery of site-directed receptor
mutants. Molecular Biology of Membrane Transport
We have cloned, sequenced and charactered peptide transport
genes from the yeast S cerevisiae, the pathogenic fungus Candida albicans,
and the plant Arabidopsis thaliana. Analysis of the peptide transport
proteins encoded by these genes indicates that we have found two new
families of eukaryotic membrane transport proteins. In addition, genes
involved in the regulation of peptide transport have been discovered. One of
these regulatory genes controls the transcription of the membrane-bound, di/tri-peptide
transport protein, and it is involved in the ubiquitin-mediated proteolytic
pathway as well. Another regulatory gene encodes a component of a novel
amino acid-inducible regulon. As the rational design of drugs against
intracellular targets must include knowledge concerning passage of these
molecules across biological membranes, this research has particular
significance to drug design and delivery. The regulation of expression of
peptide transport is studied in detail in order to uncover the relationships
among cellular metabolism, environmental sensing, and peptide transport
activity. Molecular Biology of Fungal
Pathogenesis
Fungi are increasingly important as opportunistic pathogens in humans immuno-compromised by infection with HIV, by treatment with immuno-suppressants as a result of organ transplantation, or by administration of anticancer drugs. We are interested in identifying the fungal genes encoding “virulence factors” which are those attributes that allow fungi to manifest their pathogenicity. The approach we are taking to identify such genes involves deleting genes in the fungal pathogen Candida albicans and then determining the pathogenicity of the mutated strain. We have identified a number of virulence genes in this manner. Identification of virulence genes allows delineation of targets towards which drugs can be developed by a rational approach. Proteins encoded by virulence genes are ideal targets for antifungal drugs because they are pathogen-specific. |
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