Administrative Supplement: Model-guided design of next-generation bacterial therapeutics to treat cardiovascular disease

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PROJECT SUMMARY/ABSTRACT It is becoming increasingly evident that the composition and metabolites produced by the human gut microbiome influence the progression of cardiovascular diseases. While we are continuing to discover important associations between the gut microbiome and human physiology and diseases, we lack the tools and methodology to precisely manipulate gut microbiota to benefit human health. We propose to develop computational models and optimization frameworks to predict community dynamics and functions and design interventions to shift the gut microbiome to desired states. We will design novel bacterial therapeutics that operate autonomously in the mammalian gastrointestinal tract to steer the microbiome towards healthy states. These next-generation bacterial therapeutics will sense important gut microbiome metabolites, process information, and deliver species- specific antimicrobial proteins to reshape the dynamics and functions of this ecosystem. The performance of these bacterial therapeutics will be characterized in vitro using synthetic human gut microbiome communities and in gnotobiotic mouse models of cardiovascular disease. Model-guided microbiome engineering has the potential to transform human medicine and is becoming increasingly important as scientists continue to discover connections between the microbiome and human health and disease.