Genetic Analysis of the Transcriptional Network Governing C. albicans Biofilms

描述(申请人提供)：酵母菌白色念珠菌是人类消化道的正常居民。它也是人类最常见的真菌病原体，可引起黏膜和全身感染，特别是在免疫功能低下的患者中。这项提案试图了解白色念珠菌如何协调生物膜的形成--弹性的、表面相关的、有组织的细胞团。生物膜的形成具有医学意义，因为新的白色念珠菌感染与植入的医疗设备高度相关，这些设备为生物膜的形成提供了有效的底物。在这一建议中概述的研究生物膜形成的方法是通过解剖控制这一过程的转录网络。最终目标是了解回路的单个目标基因是如何对关键做出贡献的 生物膜的特性，如耐药性、细胞间黏附、细胞间通讯和细胞外基质的产生。候选人纳比尔博士对研究有着长期的兴趣和历史。在K99的指导阶段结束后，她的职业轨迹是成为一家领先的学术研究机构的助理教授，在那里她希望继续并深化她的生物膜研究计划，履行一些教学职责，并培训未来的科学家。奈比尔博士认为，从长远来看，一旦更多地了解生物膜是如何被监管的，她的发现将为开发治疗和预防生物膜的新药和疫苗提供重要信息。这项K99/R00建议旨在补充Nobile博士之前的研究经验，并为她提供实质性和必要的技术和智力专业知识，以及作为独立调查员发挥作用的信心。她将在K99阶段接受的培训将极大地提高她的职业前景，并使她在顶级研究机构的教员职位上具有极强的竞争力。纳比尔医生的 主要导师约翰逊博士和共同导师安第斯博士的选择是经过精心挑选的，因为他们的相关、多样化和互补性的专业知识涵盖了她提案的所有要素。Mentor和Co-Mentor都有充足的资金，在各自的领域都得到了国际认可，而且非常富有成效。此外，纳比尔博士还组建了一个由不同的基础科学家和内科医生组成的顾问委员会，在她向独立研究员的转变过程中监督她的科学进步和职业发展。该委员会的所有成员都是资深科学家/医生，在指导和建议博士后过渡到独立的学术生涯方面拥有丰富的经验。 与公共卫生相关：白色念珠菌是人类最常见的真菌病原体。它在免疫能力强的人中引起表面感染，在免疫功能低下的人中引起危及生命的系统性感染。这项提案试图了解白色念珠菌是如何形成生物膜的，这是一种特别耐机械力和抗真菌药物的细胞群落。白色念珠菌在植入的医疗设备上形成生物膜，是新感染的主要来源。更详细地了解生物膜将有助于改进预防和治疗白色念珠菌感染的方法。

DESCRIPTION (provided by applicant): 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.