Project acronym BugTheDrug
Project Predicting the effects of gut microbiota and diet on an individual’s drug response and safety
Researcher (PI) Ines THIELE
Host Institution (HI) NATIONAL UNIVERSITY OF IRELAND GALWAY
Country Ireland
Call Details Starting Grant (StG), LS7, ERC-2017-STG
Summary Precision medicine is an emerging paradigm that aims at maximizing the benefits and minimizing the harm of drugs. Realistic mechanistic models are needed to understand and limit heterogeneity in drug responses. Consequently, novel approaches are required that explicitly account for individual variations in response to environmental influences, in addition to genetic variation. The human gut microbiota metabolizes drugs and is modulated by diet, and it exhibits significant variation among individuals. However, the influence of the gut microbiota on drug failure or drug side effects is under-researched. In this study, I will combine whole-body, genome-scale molecular resolution modeling of human metabolism and human gut microbial metabolism, which represents a network of genes, proteins, and biochemical reactions, with physiological, clinically relevant modeling of drug responses. I will perform two pilot studies on human subjects to illustrate that this innovative, versatile computational modeling framework can be used to stratify patients prior to drug prescription and to optimize drug bioavailability through personalized dietary intervention. With these studies, BugTheDrug will advance mechanistic understanding of drug-microbiota-diet interactions and their contribution to individual drug responses. I will perform the first integration of cutting-edge approaches and novel insights from four distinct research areas: systems biology, quantitative systems pharmacology, microbiology, and nutrition. BugTheDrug conceptually and technologically addresses the demand for novel approaches to the study of individual variability, thereby providing breakthrough support for progress in precision medicine.
Summary
Precision medicine is an emerging paradigm that aims at maximizing the benefits and minimizing the harm of drugs. Realistic mechanistic models are needed to understand and limit heterogeneity in drug responses. Consequently, novel approaches are required that explicitly account for individual variations in response to environmental influences, in addition to genetic variation. The human gut microbiota metabolizes drugs and is modulated by diet, and it exhibits significant variation among individuals. However, the influence of the gut microbiota on drug failure or drug side effects is under-researched. In this study, I will combine whole-body, genome-scale molecular resolution modeling of human metabolism and human gut microbial metabolism, which represents a network of genes, proteins, and biochemical reactions, with physiological, clinically relevant modeling of drug responses. I will perform two pilot studies on human subjects to illustrate that this innovative, versatile computational modeling framework can be used to stratify patients prior to drug prescription and to optimize drug bioavailability through personalized dietary intervention. With these studies, BugTheDrug will advance mechanistic understanding of drug-microbiota-diet interactions and their contribution to individual drug responses. I will perform the first integration of cutting-edge approaches and novel insights from four distinct research areas: systems biology, quantitative systems pharmacology, microbiology, and nutrition. BugTheDrug conceptually and technologically addresses the demand for novel approaches to the study of individual variability, thereby providing breakthrough support for progress in precision medicine.
Max ERC Funding
1 687 458 €
Duration
Start date: 2018-04-01, End date: 2023-03-31
Project acronym DC_Nutrient
Project Investigating nutrients as key determinants of DC-induced CD8 T cell responses
Researcher (PI) David FINLAY
Host Institution (HI) THE PROVOST, FELLOWS, FOUNDATION SCHOLARS & THE OTHER MEMBERS OF BOARD OF THE COLLEGE OF THE HOLY & UNDIVIDED TRINITY OF QUEEN ELIZABETH NEAR DUBLIN
Country Ireland
Call Details Consolidator Grant (CoG), LS6, ERC-2017-COG
Summary A new immunoregulatory axis has emerged in recent years demonstrating that cellular metabolism is crucial in controlling immune responses. This regulatory axis is acutely sensitive to nutrients that fuel metabolic pathways and support nutrient sensitive signalling pathways. My recent research demonstrates that nutrients are dynamically controlled and are not equally available to all immune cells. The data shows that activated T cells, clustered around a dendritic cell (DC), can consume the available nutrients, leaving the DC nutrient deprived in vitro. This local regulation of the DC nutrient microenvironment by neighbouring cells has profound effects on DC function and T cell responses. Nutrient deprived DC have altered signalling (decreased mTORC1 activity), increased pro-inflammatory functions (IL12 and costimulatory molecule expression) and induce enhanced T cell responses (proliferation, IFNγ production). However, proving this, particularly in vivo, is a major challenge as the tools to investigate nutrient dynamics within complex microenvironments have not yet been developed. This research programme will generate innovative new technologies to measure the local distribution of glucose, glutamine and leucine (all of which control mTORC1 signalling) to be visualised and quantified. These technologies will pioneer a new era of in vivo nutrient analysis. Nutrient deprivation of antigen presenting DC will then be investigated (using our new technologies) in response to various stimuli within the inflammatory lymph node and correlated to CD8 T cell responses. We will generate state-of-the-art transgenic mice to specifically knock-down nutrient transporters for glucose, glutamine, or leucine in DC to definitively prove that the availability of these nutrients to antigen presenting DC is a key mechanism for controlling CD8 T cells responses. This would be a paradigm shifting discovery that would open new horizons for the study of nutrient-regulated immune responses.
Summary
A new immunoregulatory axis has emerged in recent years demonstrating that cellular metabolism is crucial in controlling immune responses. This regulatory axis is acutely sensitive to nutrients that fuel metabolic pathways and support nutrient sensitive signalling pathways. My recent research demonstrates that nutrients are dynamically controlled and are not equally available to all immune cells. The data shows that activated T cells, clustered around a dendritic cell (DC), can consume the available nutrients, leaving the DC nutrient deprived in vitro. This local regulation of the DC nutrient microenvironment by neighbouring cells has profound effects on DC function and T cell responses. Nutrient deprived DC have altered signalling (decreased mTORC1 activity), increased pro-inflammatory functions (IL12 and costimulatory molecule expression) and induce enhanced T cell responses (proliferation, IFNγ production). However, proving this, particularly in vivo, is a major challenge as the tools to investigate nutrient dynamics within complex microenvironments have not yet been developed. This research programme will generate innovative new technologies to measure the local distribution of glucose, glutamine and leucine (all of which control mTORC1 signalling) to be visualised and quantified. These technologies will pioneer a new era of in vivo nutrient analysis. Nutrient deprivation of antigen presenting DC will then be investigated (using our new technologies) in response to various stimuli within the inflammatory lymph node and correlated to CD8 T cell responses. We will generate state-of-the-art transgenic mice to specifically knock-down nutrient transporters for glucose, glutamine, or leucine in DC to definitively prove that the availability of these nutrients to antigen presenting DC is a key mechanism for controlling CD8 T cells responses. This would be a paradigm shifting discovery that would open new horizons for the study of nutrient-regulated immune responses.
Max ERC Funding
1 995 861 €
Duration
Start date: 2018-05-01, End date: 2023-04-30
