Our lab exploits whole genome approaches to tackle
problems in yeast molecular biology and human infectious disease.
These projects can be classified into three separate areas:
Functional genomics of Plasmodium falciparum, the causative agent
of human malaria.
Malaria is one of the most deadly and profound human health problems
in existence and results in approximately 1.5 to 2.7 million deaths
annually. The most fatal and prevalent form of malaria is caused by
the blood-borne pathogen Plasmodium falciparum. Beyond the lives this
parasite claims every year, hundreds of millions of people will become
clinically ill. The socioeconomic impact of this disease to developing
countries, especially those on the African continent, is beyond measure.
There exist no vaccines with an operational impact and resistance
of the parasite to current anti-malarial drugs has spread worldwide.
Because the vast majority of malaria occurs in poor nations, there
is little profit incentive for large western and European drug companies
to pursue new anti-malarial therapies, yet novel approaches are in
desperate need
The paucity of new anti-malarial medications is partly attributable
to the lack of validated drug targets. Indeed, all currently
approved drugs and those in development are directed against only
a handful of gene products and processes. Unlike many bacterial pathogens,
both genetic and molecular biological approaches have been difficult
in Plasmodia. Fortunately, the completion of the Plasmodium falciparum
sequencing project will inherently broaden the range of potential
drug targets by identifying all possible open reading frames. Although
a great deal of functional annotation may be accomplished by sequence
based homology comparisons, this information will not be sufficient
to determine whether a gene product actually participates in a function
or process at any given time during the development of the parasite.
In addition, the majority of gene products discovered through the
sequencing of the genome will not reveal significant sequence homology
and therefore will remain hypothetical and uncharacterized. We are
utilizing the full potential of the completed sequence by implementing
a functional genomics approach to the elucidation of metabolic and
stage specific gene expression. This is being accomplished by systematic
perturbation of P. falciparum cultures in conjunction with genome
wide gene expression profiling, exhaustive homology based sequence
comparison, pathway analysis, and functional characterization.
Whole genome approaches to the molecular biology of Saccharomyces
cerevisiae
We are using DNA microarrays to investigate several different aspects
of yeast biology. These include chromatin immunoprecipitation techniques
to reconstruct the protein-DNA topology of the genome, gene expression
profiles to investigate the action of small molecule drugs, and immunoprecipitation
of RNA binding proteins to screen for novel regulatory mechanisms.
Other yeast-based projects in the lab seek to elucidate the mechanisms
responsible for the various steps of meiotic recombination through
genetics and biochemistry.
Searching for a link between asthma and viral infection.
The notion that acute asthma attacks are frequently precipitated by
respiratory infection is part of the training of every physician and
is well supported in general terms by numerous clinical investigations.
However, the prevalence of respiratory infection in acute asthma and
the identities of the responsible pathogen(s) have been more controversial.
Studies based upon culture and/or viral antigen detection in respiratory
secretions of asthmatics have generally recorded rates of infection
between 20-40%; these studies typically identify rhinoviruses, coronaviruses,
adenoviruses, influenza and parainfluenza viruses. This is likely
to be an underestimate and likely define a minimal estimate of the
contribution of viral infection to acute asthma attacks.
We are constructing and using a viral DNA microarray based system
customized for the goal of detecting and differentiating between pathogens
commonly found in the respiratory tract. This technology will allow
us to investigate whether there is a positive correlation between
viral infection and asthma attacks, if so, which viral types are so
associated. To accomplish this goal, we are actively collaborating
with an on-going clinical research study of asthma here at UCSF. |
Gerton, J. L., DeRisi, J., Shroff, R., Lichten,
M., Brown, P. O., and Petes, T. D. Inaugural article: global mapping
of meiotic recombination hotspots and coldspots in the yeast saccharomyces
cerevisiae [In Process Citation]. (2000) Proc Natl Acad Sci U S
A 97(21), 11383-90
Hayward, R. E., Derisi, J. L., Alfadhli, S., Kaslow, D. C., Brown,
P. O., and Rathod, P. K. Shotgun DNA microarrays and stage-specific
gene expression in Plasmodium falciparum malaria. (2000) Mol Microbiol
35(1), 6-14
Ogawa, N., DeRisi, J., and Brown, P. O. New Components of a System
for Phosphate Accumulation and Polyphosphate Metabolism in Saccharomyces
cerevisiae Revealed by Genomic Expression Analysis. (2000) Mol Biol
Cell 11(12), 4309-4321
Takizawa, P. A., DeRisi, J. L., Wilhelm, J. E., and Vale, R. D.
Plasma membrane compartmentalization in yeast by messenger RNA transport
and a septin diffusion barrier [In Process Citation]. (2000) Science
290(5490), 341-4
Chu, S., DeRisi, J., Eisen, M., Mulholland, J., Botstein, D., Brown,
P. O., and Herskowitz, I. The transcriptional program of sporulation
in budding yeast [published erratum appears in Science 1998 Nov
20;282(5393):1421]. (1998) Science 282(5389), 699-705
DeRisi, J. L., Iyer, V. R., and Brown, P. O. Exploring the metabolic
and genetic control of gene expression on a genomic scale. (1997)
Science 278(5338), 680-6
information last updated February 2003 |
Biomedical Sciences (BMS) Graduate Program
