The applicant is currently an experienced post-doctoral fellow transitioning into a role as an independent investigator. Immediate career objectives are to complete current research and obtain bridging resources to facilitate the establishment of an academic research position. The K22 award and career development plans would link within the long-term career objectives of developing an internationally-recognized laboratory investigating fungi that cause human disease or allergy. ? ? Light influences many properties in species of fungi, such as regulating sexual or asexual sporulation, pigment production, phototropism, and setting a circadian clock. The BWC1 and BWC2 genes, encoding a putative photoreceptor and interacting transcription factor, control inhibition of mating by light, tolerance to UV irradiation, and virulence in the human pathogenic fungus Cryptococcus neoformans. However, it is unclear what genes are regulated by light via Bwc1-Bwc2. Their identification, through this research, will provide directions towards controlling fungal infectious disease. ? ? Aim 1 is to identify genes regulated by light using a whole genome microarray analysis of transcription, comparing a wild type strain grown in constant darkness or treated with a pulse of light.
Aim 2 is to demonstrate that the promoters of light-regulated genes physically interact with Bwc1-Bwc2 by gel mobility shift assays. Preliminary studies have revealed 30 genes that are light-regulated. One such gene encodes ferrochelatase, which catalyzes the final step of heme biosynthesis from protoporphyrin IX. Heme is an essential co-factor in many proteins, while porphyrins are highly photoreactive.
Aim 3 will test the hypothesis that ferrochelatase activity is a major factor that mediates C. neoformans sensitivity to light and virulence. Strains with altered expression levels of ferrochelatase will be constructed and their phenotypes tested for mating, UV sensitivity and virulence in a macrophage cell line model. ? ? The relevance of the research is that it will enable the discovery of new genes that enable fungi to be virulent towards humans and to spread in nature. This information is expected to provide strategies to minimize exposure to fungal inocula to reduce initial infection or exposure to spores that cause allergies, and enable the design of strategies to use light as a therapy against fungal diseases. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Career Transition Award (K22)
Project #
1K22AI073917-01
Application #
7249522
Study Section
Microbiology and Infectious Diseases B Subcommittee (MID)
Program Officer
Duncan, Rory A
Project Start
2007-09-15
Project End
2009-07-31
Budget Start
2007-09-15
Budget End
2008-07-31
Support Year
1
Fiscal Year
2007
Total Cost
$161,400
Indirect Cost
Name
University of Missouri Kansas City
Department
Type
DUNS #
010989619
City
Kansas City
State
MO
Country
United States
Zip Code
64110
Magditch, Denise A; Liu, Tong-Bao; Xue, Chaoyang et al. (2012) DNA mutations mediate microevolution between host-adapted forms of the pathogenic fungus Cryptococcus neoformans. PLoS Pathog 8:e1002936
Idnurm, Alexander (2011) Sex and speciation: the paradox that non-recombining DNA promotes recombination. Fungal Biol Rev 25:121-127
Idnurm, Alexander; Verma, Surbhi; Corrochano, Luis M (2010) A glimpse into the basis of vision in the kingdom Mycota. Fungal Genet Biol 47:881-92
Idnurm, Alexander; Heitman, Joseph (2010) Ferrochelatase is a conserved downstream target of the blue light-sensing White collar complex in fungi. Microbiology 156:2393-407
Idnurm, Alexander (2010) A tetrad analysis of the basidiomycete fungus Cryptococcus neoformans. Genetics 185:153-63
Sanz, Catalina; Rodríguez-Romero, Julio; Idnurm, Alexander et al. (2009) Phycomyces MADB interacts with MADA to form the primary photoreceptor complex for fungal phototropism. Proc Natl Acad Sci U S A 106:7095-100
Ma, Li-Jun; Ibrahim, Ashraf S; Skory, Christopher et al. (2009) Genomic analysis of the basal lineage fungus Rhizopus oryzae reveals a whole-genome duplication. PLoS Genet 5:e1000549
Idnurm, Alexander; Walton, Felicia J; Floyd, Anna et al. (2009) Identification of ENA1 as a virulence gene of the human pathogenic fungus Cryptococcus neoformans through signature-tagged insertional mutagenesis. Eukaryot Cell 8:315-26
Idnurm, Alexander; Crosson, Sean (2009) The photobiology of microbial pathogenesis. PLoS Pathog 5:e1000470