Enabling personalised diagnosis, treatment, and stratification through whole-body metabolic modelling of an individual’s genome, metabolome, and metagenome.

Descripción del proyecto

Modelos innovadores de metabolismo corporal total para la medicina personalizada

Cada vez se dispone de más secuencias genómicas completas, lo que facilita la transición a la medicina personalizada. Sin embargo, es esencial comprender qué variantes genéticas influyen en las características de una persona. Los estudios de asociación del genoma completo han relacionado las variantes genéticas con numerosos rasgos, pero estos métodos no tienen en cuenta la red bioquímica que conecta estas variantes con el fenotipo metabólico. Factores externos como la alimentación y el microbioma también desempeñan un papel en la modulación del fenotipo metabólico. El equipo del proyecto AVATAR, financiado por el Consejo Europeo de Investigación, tiene como objetivo desarrollar un nuevo marco de modelización computacional para mejorar los modelos de metabolismo corporal total. Creará modelos «in silico» que expliquen las variantes genéticas, los genes, las proteínas, las reacciones bioquímicas y los procesos fisiológicos subyacentes que afectan al metabolismo microbiano y de los nutrientes. En AVATAR se proporcionará un marco de análisis de modelos personalizados para estrategias de diagnóstico y tratamiento guiadas por ordenador.

Objetivo

The increasing availability of whole-genome sequences will ultimately transform medicine into personalised medicine. To realise this potential, we need to understand which of the millions of genetic variants in a person’s genome can alter a phenotype. Genome-wide association studies (GWAS) have associated many genetic variants with thousands of phenotypic traits. Metabolomics has further informed GWAS. However, these methods do generally not consider the biochemical network connecting genetic variants with the metabolic phenotype. Additionally, extrinsic factors, such as diet and the microbiome, also modulate the metabolic phenotype. A computational systems approach is required to untangle this complex interplay. In AVATAR, I shall develop and apply a novel mechanistic computational modelling framework that will significantly expand cutting-edge computational models of whole-body metabolism. The novel in silico models will mechanistically describe the network of genetic variants, genes, proteins, and biochemical reactions, as well as underlying physiological processes that are influenced by microbial and nutrient metabolism. I shall devise a novel algorithm to predict phenotypically relevant genetic variants based on a person’s genome and metabolome. The validated algorithm and the modelling framework shall then be used for two distinct biomedical proof-of-concept studies: the diagnosis and diet-based treatment of inherited metabolic diseases and the metabolic pathway-based stratification of individuals with cognitive impairment. AVATAR will enable novel insights into the genotype-phenotype-environment relationship by enabling systematic mechanism-based analyses of genetic variants, diet, and the microbiome. This ground-breaking, innovative, multidisciplinary project will influence precision medicine by providing a personalisable modelling analysis framework that may ultimately provide a foundation for computer-guided diagnosis and treatment strategies.