Saturday, December 21, 2024
12/21/2024
Project Abstract The goal of this work is to develop a universal toolkit to facilitate detailed mapping of interactions within the gastrointestinal (GI) microbiome, and interactions between the GI microbiome and host cells. The successful completion of the proposed research will enable the prescriptive manipulation of the GI microbiome to achieve desired physiologic effects – advancing the fundamental understanding of what constitutes a “healthy” GI microbiome. Clinicians and researchers have established clear qualitative correlations between GI microbiota composition and various aspects of human health. While scientists have made great progress in observing genotypic and phenotypic outcomes of the GI microbiome, researchers and clinicians do not know how to prescriptively alter (or induce) the GI microbiome to achieve a desired effect. To accomplish this objective will first require a detailed understanding and map of the myriad interactions between GI bacteria, in addition to the microbiome and the host – both of which are currently unrealized. This is due in part to the lack of domesticated bacteria (i.e., less than 1%) from the GI microbiome, and the lack of universal tools that can be used to study various interactions (selectively and systematically) across species, phylum, and kingdom. To resolve the gaps in knowledge and related technical ability, over the next 5 years this research will concentrate on domesticating an additional 2-5% of the GI microbiome (20-50 bacterial species), focused on three major GI phyla – i.e., Bacteroidetes, Firmicutes, and Actinobacteria. Domestication will include universal tool development enabling programmable gain-of-function and loss-of-function within a given bacteria and between bacteria in defined mock microbial communities. The toolkit will consist of two fundamental operations – (i) synthetic decision-making, and (ii) synthetic memory – that can be deployed in a multiplexed format for concurrent and sequential experimental assessment of interactions between cells. Decision-making will facilitate the programmed regulation of coding and non-coding RNA via a reversible (or transient) modality – e.g., enabling ON-OFF-ON and OFF-ON-OFF operations. Programmable synthetic memory will facilitate inheritable changes that will enable mimicry of horizontal gene transfer and evolution within the microbiome. Finally, this research will enable the development of mock ecosystems to facilitate the general study of microbe host (organoid) interactions. The bottom-up construction of mock ecosystems will permit the investigation of reduced complexity assemblages with greater control increasing the ability to define specific interactions and result in faster and more robust outcomes.
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