The yeast Candida albicans is a normal resident of the human digestive tract. It is also the most common fungal pathogen of humans, causing both mucosal and systemic infections, particularly in immune compromised patients. This proposal seeks to understand how C. albicans orchestrates the formation of biofilms - resilient, surface-associated, organized groups of cells. Biofilm formation is medically relevant because new C. albicans infections are highly correlated with implanted medical devices, which provide efficient substrates for biofilm formation. The approach to studying biofilm formation outlined in this proposal is through dissection of the transcriptional network that controls this process. The ultimate goal is to understand how the individual target genes of the circuit contribute to the key properties of biofilms, such as drug resistance, cell-cell adhesion, cell-cell communication, and production of extracellular matrix. The candidate, Dr. Nobile, has a longstanding interest and history in research. Her career trajectory after the mentored phase of this K99 is to become an assistant professor at a leading academic research institute, where she hopes to continue and further her research program on biofilms, perform some teaching responsibilities, and train future scientists. Dr. Nobile believes that in the long-term, once more is known about how biofilms are regulated, her findings will provide important information to developing new drugs and vaccines to treat and prevent them. This K99/R00 proposal is designed to complement Dr. Nobile's prior research experience and to provide her with substantive and necessary technical and intellectual expertise as well as the confidence to function as an independent investigator. The training she will receive in the K99 phase will substantially enhance her career prospects, and make her highly competitive for faculty positions in top tier research institutes. Dr. Nobile's choices of primary mentor, Dr. Johnson, and co-mentor, Dr. Andes, were carefully selected for their relevant, diverse, and complementary expertise to cover all elements of her proposal. Both mentor and co-mentor are well-funded, internationally-recognized in their respective fields, and extremely productive. In addition, Dr. Nobile has assembled an advisory committee consisting of a diverse group of basic scientists and physicians to oversee her scientific progression and career development throughout her transition to becoming an independent investigator. All members of this committee are senior scientists/physicians with extensive experience in mentoring and advising postdocs as they transition to an independent academic career.

Public Health Relevance

C. albicans is the most prevalent human fungal pathogen. It causes superficial infections in immunocompetent humans and life threatening, systemic infections in immunocompromised individuals. This proposal seeks to understand how C. albicans forms biofilms, communities of cells particularly resistant to mechanical force and antifungal drugs. C. albicans biofilms formed on implanted medical devices and are a major source of new infections. Understanding biofilms in more detail will lead to improvements in preventing and treating C. albicans infections.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Transition Award (R00)
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No Study Section (in-house review) (NSS)
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Duncan, Rory A
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University of California Merced
Earth Sciences/Resources
United States
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Giosa, Domenico; Felice, Maria Rosa; Lawrence, Travis J et al. (2017) Whole RNA-Sequencing and Transcriptome Assembly of Candida albicans and Candida africana under Chlamydospore-Inducing Conditions. Genome Biol Evol 9:1971-1977
Lohse, Matthew B; Gulati, Megha; Valle Arevalo, Ashley et al. (2017) Assessment and Optimizations of Candida albicans In Vitro Biofilm Assays. Antimicrob Agents Chemother 61:
Srivastava, Archita; Sircaik, Shabnam; Husain, Farha et al. (2017) Distinct roles of the 7-transmembrane receptor protein Rta3 in regulating the asymmetric distribution of phosphatidylcholine across the plasma membrane and biofilm formation in Candida albicans. Cell Microbiol 19:
Jenull, Sabrina; Tscherner, Michael; Gulati, Megha et al. (2017) The Candida albicans HIR histone chaperone regulates the yeast-to-hyphae transition by controlling the sensitivity to morphogenesis signals. Sci Rep 7:8308
Liang, Weihong; Guan, Guobo; Dai, Yu et al. (2016) Lactic acid bacteria differentially regulate filamentation in two heritable cell types of the human fungal pathogen Candida albicans. Mol Microbiol 102:506-519
Hernday, Aaron D; Lohse, Matthew B; Nobile, Clarissa J et al. (2016) Ssn6 Defines a New Level of Regulation of White-Opaque Switching in Candida albicans and Is Required For the Stochasticity of the Switch. MBio 7:e01565-15
Lohse, Matthew B; Kongsomboonvech, Pisiwat; Madrigal, Maria et al. (2016) Genome-Wide Chromatin Immunoprecipitation in Candida albicans and Other Yeasts. Methods Mol Biol 1361:161-84
Vargas, Derek; Hageman, Samantha; Gulati, Megha et al. (2016) S-nitrosomycothiol reductase and mycothiol are required for survival under aldehyde stress and biofilm formation in Mycobacterium smegmatis. IUBMB Life 68:621-8
Winter, Michael B; Salcedo, Eugenia C; Lohse, Matthew B et al. (2016) Global Identification of Biofilm-Specific Proteolysis in Candida albicans. MBio 7:
Gulati, Megha; Nobile, Clarissa J (2016) Candida albicans biofilms: development, regulation, and molecular mechanisms. Microbes Infect 18:310-21

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