The Interactive Metabolome of Polymicrobial Biofilms

描述（由申请人提供）：这是一份K 01奖的申请书，申请人是加州大学圣地亚哥分校斯卡格斯药学和药物科学学院药理学系的化学家Vanessa Dallan博士。Dr. Rehan正在将自己打造成一名年轻的研究人员，从事多微生物生物膜的代谢组学研究。该K 01奖项将为Dr. Dallan提供必要的支持，以实现以下目标：（1）成为阐明复杂微生物群落中化学串扰的专家;（2）对与囊性纤维化肺部感染相关的多微生物生物膜内的复杂代谢交换进行临床相关研究;（3）实施最先进的质谱技术来研究混合生物膜;（4）开发生物膜内生物体和代谢物的因果预测模型;（5）发展独立的研究生涯。为了实现这些目标，Dr. Dallan组建了一个指导团队，由主要导师，UCSD Skaggs药学和制药科学学院副教授Pieter Dorrestein博士和一位共同导师组成，他对微生物的代谢交换进行学术研究：加州大学医学系助理教授苏珊娜·诺布尔博士，San弗朗西斯科，她在微生物遗传学方面的专长主要集中在C。白色念珠菌、共分离株和哺乳动物宿主。 众所周知，微生物产生用于种内和种间相互作用的小分子。然而，这些代谢产物在较大的多微生物生物膜群落中的作用仍未得到研究。Dr. Rehan的研究将专注于定义负责建立和维持来自囊性纤维化肺部感染的共分离物的多微生物生物膜群落的代谢物（目标1），通过基因敲除或引入抗生素的亚抑制浓度（目标2）去除关键代谢物来扰乱这些群落的影响，并开发生物体的预测分子网络（目标3）。Dr. Dallan将使用最先进的质谱法，包括微生物菌落的二维和三维成像质谱法，以及一种能够直接从培养皿中采样微生物菌落的新技术。这项研究将为微生物生物膜的多重研究奠定基础，包括蛋白质组学，转录组学和代谢组学相互作用，将在K奖结束前在R 01资助申请中提出。 公共卫生相关性：对人类致病微生物与其环境之间潜在相互作用的更好理解提供了对疾病基本原因的深入了解。在这个项目中，我们将识别病原体用来与环境相互作用的分子。

DESCRIPTION (provided by applicant): This is an application for a K01 award for Dr. Vanessa Phelan, a chemist in the Department of Pharmacology at Skaggs School of Pharmacy and Pharmaceutical Sciences at the University of California, San Diego. Dr. Phelan is establishing herself as a young investigator in research of the metabolomics of polymicrobial biofilms. This K01 award will provide Dr. Phelan with the support necessary to accomplish the following goals: (1) to become expert at elucidating the chemical crosstalk in complex microbial communities; (2) to conduct clinically relevant investigations of the complex metabolic exchange within polymicrobial biofilms associated with cystic fibrosis lung infections; (3) to implement state-of-the-art mass spectrometry techniques to investigate mixed biofilms; (4) to develop a causal predictive model of the organisms and metabolites within biofilms and (5) to develop an independent research career. To achieve these goals, Dr. Phelan has assembled a mentoring team comprised of a primary mentor, Dr. Pieter Dorrestein, Associate Professor in Skaggs School of Pharmacy and Pharmaceutical Sciences, UCSD, who conducts academic research into metabolic exchange of microorganisms and one co-mentor: Dr. Suzanne Noble, an Assistant Professor in the Department of Medicine at University of California, San Francisco whose expertise in microbial genetics focuses her work on the interactions between C. albicans, co-isolates and the mammalian host. It is well established that microorganisms produce small molecules for both intra-species and inter- species interactions. However, the roles of these metabolites in the larger polymicrobial biofilm community remain uninvestigated. Dr. Phelan's research will focus on defining the metabolites responsible for establishing and maintaining a polymicrobial biofilm community derived of co-isolates from cystic fibrosis lung infections (Aim 1), the effect of perturbing these communities by removing key metabolites via gene knock-outs or introducing sub-inhibitory concentrations of antibiotics (Aim 2) and developing a predictive molecular network of the organisms (Aim 3). Dr. Phelan will use state-of-the-art mass spectrometry including two-dimensional and three-dimensional imaging mass spectrometry of microbial colonies and a new technique capable of sampling a microbial colony directly from a petri-dish. This research will form the basis for a multiplexed study of microbial biofilms includig proteomic, transcriptomic and metabolomic interactions to be proposed in an R01 grant application before the end of the K award. PUBLIC HEALTH RELEVANCE: Improved understanding of the underlying interactions between human disease causing organisms and their environment provides insight into the basic cause of disease. In this project we will identify the molecules that pathogens use to interact with their environment.