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.
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.
|Nobile, Clarissa J; Fox, Emily P; Hartooni, Nairi et al. (2014) A histone deacetylase complex mediates biofilm dispersal and drug resistance in Candida albicans. MBio 5:e01201-14|
|Fox, Emily P; Cowley, Elise S; Nobile, Clarissa J et al. (2014) Anaerobic bacteria grow within Candida albicans biofilms and induce biofilm formation in suspension cultures. Curr Biol 24:2411-6|
|Tao, Li; Du, Han; Guan, Guobo et al. (2014) Discovery of a "white-gray-opaque" tristable phenotypic switching system in candida albicans: roles of non-genetic diversity in host adaptation. PLoS Biol 12:e1001830|
|Kavanaugh, Nicole L; Zhang, Angela Q; Nobile, Clarissa J et al. (2014) Mucins suppress virulence traits of Candida albicans. MBio 5:e01911|
|Tao, Li; Cao, Chengjun; Liang, Weihong et al. (2014) White cells facilitate opposite- and same-sex mating of opaque cells in Candida albicans. PLoS Genet 10:e1004737|
|Johnson, Larry; Gaab, Erin M; Sanchez, Javier et al. (2014) Valley fever: danger lurking in a dust cloud. Microbes Infect 16:591-600|
|Lin, Ching-Hsuan; Kabrawala, Shail; Fox, Emily P et al. (2013) Genetic control of conventional and pheromone-stimulated biofilm formation in Candida albicans. PLoS Pathog 9:e1003305|
|Xie, Jing; Tao, Li; Nobile, Clarissa J et al. (2013) White-opaque switching in natural MTLa/Î± isolates of Candida albicans: evolutionary implications for roles in host adaptation, pathogenesis, and sex. PLoS Biol 11:e1001525|
|Guan, Guobo; Xie, Jing; Tao, Li et al. (2013) Bcr1 plays a central role in the regulation of opaque cell filamentation in Candida albicans. Mol Microbiol 89:732-50|
|Hernday, Aaron D; Lohse, Matthew B; Fordyce, Polly M et al. (2013) Structure of the transcriptional network controlling white-opaque switching in Candida albicans. Mol Microbiol 90:22-35|
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