Department of Pathology & Laboratory Medicine
INFECTIOUS DISEASES:
Fungal PathogenesisDr. Judith Rhodes continues her studies on genes encoding factors involved in nutritional sensing and response and stress response in Aspergillus fumigatus. Her current work is focused on the protein kinase A pathway in stress response and the Ras signaling pathway in directing growth polarity. Mutants with unregulated PKA produce conidia that have increased sensitivity to oxidative damage. Their growth is also compromised. These changes lead to decreased virulence ina murine model of invasive aspergillosis. The lab is now working with the Proteomics Core at the GRI to compare the phosphoproteome of the wild type to that of a mutant lacking the type I catalytic subunit, so that direct and indirect targets of the kinase can be identified. Control of growth polarity is necessary for invasive growth of the organism. A novel Ras protein, which is unique to filamentous fungi, appears to regulate the polarity axis and branch points. Mutational studies have identified a region of the molecule required for function, and now fine mapping and localization of fluorescently labeled proteins will be used to understand the mechanism of action. Dr. Rhodes collaborates with Dr. David Askew in studying the regulation of growth in A. fumigatus.
Dr. Askew's lab is interested in understanding how A. fumigatus balances biosynthetic and degradative processes to optimize its growth. As a major component of the biomass in a self-heating compost pile, A. fumigatus has evolved mechanisms that allow it to grow rapidly at 37oC. The Askew Lab has shown that this requires CgrA, a nucleolar protein involved in ribosome biogenesis. Their objective is to understand how CgrA promotes thermotolerance, with the long-term goal of identifying new strategies to disrupt the growth of the organism at 37oC.
A second project involves analysis of the fungal programmed cell death (PCD) machinery. PCD has been divided into two major categories based on the effectors involved: caspase-dependent PCD (type I) and autophagy-dependent PCD (type II). Comparisons between mammalian and fungal genomes indicate that both of these pathways exist in lower eukaryotes. However, little is understood about their nature and function in filamentous fungi. The goal of the lab is to characterize the molecules involved in these pathways, and to understand their contribution to the growth and virulence of A. fumigatus.
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