Melanin is a pigment that performs a variety of functions and is found in the plant and animal kingdoms. In fungi melanin reinforces cell walls, shields against ultraviolet radiation as well as toxic metals, harnesses high energy electromagnetic radiation and contributes to virulence. Despite its importance, very little is known about the structure of melanin because it is insoluble and amorphous, making it difficult to analyze. In the previous funding period we described a new, melanin-based process for harnessing energy through the capture of radiation; we laid the foundation for a new melanoma therapy targeting melanin that is now in clinical trials; we demonstrated the remarkable ability of melanin to shield against radiation and provided a novel way to study the structure of melanin by solid-state NMR analysis; we discovered an extracellular vesicular transport in fungi (associated with the formation of a fungal melanosome). This research program renewal is focused on melanization in the human pathogenic fungus Cryptococcus neoformans, which is responsible for almost a million annual cases of meningitis worldwide, primarily in patients with AIDS. We will build on the achievements and tools of the previous funding period in order to focus on the fungal melanosome and the process of melanization.
Three Specific Aims are proposed: 1) To generate a molecular definition for the cargo in melanizing vesicle populations; 2) To investigate the mechanism by which the fungal melanosome interacts with the cell wall; 3) To investigate the molecular structure of C. neoformans melanin assemblies on their cell-wall scaffold. C. neoformans melanin is critical for virulence and it is also a potential target for therapeutic drug development. Agents that target melanin are attractive because they could be applied against a broad array of pathogenic fungi.
Melanin is a complex pigment that is involved in numerous biological processes from protection against sunlight to energy harvest. Melanin also contributes to fungal virulence by undermining host defense mechanisms and melanized fungi are much less resistant to certain antifungal drugs. This proposal seeks to understand how melanin is made in an important human pathogenic fungus because this information is of fundamental importance for understanding fungal cell biology and can potentially lead to new therapies that target melanization pathways.
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