Cryptococcus neoformans is
a clinically important fungal pathogen that
has been utilized extensively to study molecular
mechanisms that contribute to fungal pathogenesis.
Immunocompromised patients, such as those with
AIDS are most susceptible to infection by C.
neoformans. In these patients, dissemination
of C. neoformans from the lungs to
the central nervous system can result in cryptococcal
meningoencephalitis, a life-threatening disease.
In healthy individuals, the infection is often
asymptomatic and self-resolving.
The focus of my research
in Dr. Christina Hull's lab is to investigate
the role of key regulators of C. neoformans
sexual development in the production of
spores, which are believed to be the infectious
propagule. The most common infectious propagules
produced by the pathogenic fungi are spores,
which can result from the process of sexual
development. During sexual development,
haploid cells of opposite mating type (a
and a) fuse and form a binucleate
cell that undergoes a transition from yeast-form
to filamentous growth. The resulting filaments
(known as dikaryons) ultimately differentiate
into a specialized structure in which meiosis
and spore formation occurs.
Sexual development in C.
neoformans is regulated by the S e
x I nducer genes SXI a
and SXI2a, which
are specific to a
and a cells, respectively.
Mating studies with sxi1aD
mutant strains indicate that Sxi1a
and Sxi2a are dispensable
in haploid cells but are required for establishment
of the dikaryon. The mechanisms by which Sxi1a
and Sxi2a regulate sexual
development are unknown. My goal is to use microarray
analysis to elucidate the regulatory circuitry
controlled by Sxi1a
and Sxi2a. Whole genome C.
neoformans spotted microarrays consisting
of 70-mer oligos that represent 7738 predicted
open reading frames will be used. We have established
parameters that define early, mid, and late
stages of sexual development. The rationale
for looking at different stages within the developmental
process is that Sxi1a
and Sxi2a may have different
roles in regulating sexual development relative
to the stage of the developmental process. We
anticipate that these experiments will elucidate
the identity of constituents of the regulatory
circuitry that are controlled by Sxi1a
and Sxi2a. Preliminary results
from a pilot microarray experiment have identified
genes that were previously shown to be involved
in regulating sexual development. Exploration
of the regulatory circuitry that controls sexual
development will provide insight into mechanisms
that facilitate spore formation, which in turn
is key to understanding the relationship between
the biology of C. neoformans and pathogenesis.
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