CAREER: Elucidating the Roles of Extracellular Metal Ions in Gut Microbiota Interactions

在化学系生命过程化学项目的支持下，休斯顿大学的梅丽莎·扎斯特罗正在研究金属离子如何影响肠道微生物群中的细胞-细胞和细胞-宿主相互作用。金属离子如钙、铁和锌在生物学中起着关键的调节、催化和结构作用。在肠道菌群中，这些基本元素可用性的变化与不同细菌物种的定植变化以及感染和疾病有关，但潜在的分子机制尚不清楚。这项拟议的研究调查了金属如何影响细菌和宿主蛋白质之间的相互作用。揭示金属如何影响肠道微生物群的分子机制可以导致新的治疗方法，并为更有效地利用当前的医学治疗提供指导。这些研究将与一个交互式生物无机训练项目的发展相结合，即“生物界面上的无机化学”（ICBI）研讨会，该研讨会的重点是研究金属离子在生物界面上的作用，并为本科生和研究生量身定制。参与的学生将有机会从事跨学科的研究，同时促进他们作为科学家的成长。该研究项目的重点是阐明金属影响肠道微生物群中细胞-细胞和细胞-宿主相互作用的基本机制。数以百计的微生物物种共存于胃肠道中，并可通过细胞-细胞或细胞-宿主相互作用相互作用。金属的变化可以通过与细菌细胞表面（包括表面蛋白）或粘蛋白等宿主蛋白结合来增强或破坏这些相互作用。这项工作将利用乳酸菌科的细菌，结合生化和分析方法来确定金属影响细菌-细胞相互作用和细菌-宿主黏蛋白之间的细胞-宿主相互作用的机制。为了测试金属对细胞-细胞相互作用的影响，将使用生化和微观表征来测量单物种和多物种系统中生物膜的形成。类似的技术将用于探测单一和多物种系统中的细胞-粘蛋白相互作用。位点定向诱变将用于研究表面蛋白金属结合位点在介导细胞-细胞和细胞-宿主相互作用中的作用。总的来说，这些研究将验证金属可以通过与特定细胞表面大分子和宿主蛋白质结合来介导肠道微生物群中细菌相互作用的假设。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

With the support of the Chemistry of Life Processes program in the Division of Chemistry, Melissa Zastrow of the University of Houston is studying how metal ions affect cell-cell and cell-host interactions in the gut microbiota. Metal ions such as calcium, iron, and zinc play critical regulatory, catalytic, and structural roles in biology. In gut microbiota, changes to the availability of these essential elements are linked to changes in the colonization of different bacterial species along with infection and disease, but the underlying molecular mechanisms are unclear. The proposed research investigates how metals affect interactions between bacteria and host proteins. Uncovering molecular mechanisms for how metals affect the gut microbiota can lead to novel therapeutics and provide guidance for more effective use of current medical treatments. These studies will be integrated with the development of an interactive bioinorganic training project, the “Inorganic Chemistry at Biological Interfaces” (ICBI) workshop, which is centered on investigating the roles of metal ions at biological interfaces and tailored to undergraduate and graduate students. Participating students will have the opportunity to engage in interdisciplinary research while furthering their growth as scientists.This research project centers on elucidating the fundamental mechanisms through which metals affect cell-cell and cell-host interactions in the gut microbiota. Hundreds of microbial species co-exist in the gastrointestinal tract and can interact via cell-cell or cell-host interactions. Changes in metals could enhance or disrupt these interactions by binding to bacterial cell surfaces, including surface proteins, or host proteins such as mucins. The proposed work will use bacteria from the Lactobacillaceae family and a combination of biochemical and analytical methods to establish mechanisms through which metals affect 1) bacterial cell-cell interactions and 2) cell-host interactions between bacteria and host mucin proteins. To test the effects of metals on cell-cell interactions, biochemical and microscopic characterization will be used to measure biofilm formation in single and multi-species systems. Similar techniques will be used to probe cell-mucin interactions in single and multi-species systems. Site-directed mutagenesis will be used to study the role of surface protein metal-binding sites in mediating both cell-cell and cell-host interactions. Collectively, these studies will test the hypothesis that metals can mediate bacterial interactions in gut microbiota by binding to specific cell surface macromolecules and host proteins.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.