Integrative metabolomics and genomics analysis for the development of markers of inherited kidney diseases: a personalised medicine approach

Descripción del proyecto

Análisis metabolómico y genómico de nefropatías raras

Las nefropatías hereditarias raras son un grupo de trastornos heterogéneos que a menudo requieren el trasplante de riñón, lo que compromete seriamente la calidad de vida de los pacientes. El objetivo del proyecto financiado con fondos europeos MODIRen es solventar la falta de biomarcadores para el diagnóstico, la prognosis y la terapia de este conjunto de trastornos. Los investigadores llevarán a cabo una secuenciación del exoma completo para identificar variantes genéticas y emplearán un método de fenotipado profundo para determinar marcadores metabólicos específicos de las nefropatías hereditarias raras. Estos datos, junto con información clínica, proporcionarán firmas de genotipo-fenotipo y ayudarán a determinar la fisiopatología de las nefropatías hereditarias raras. Los resultados del proyecto servirán de base para la mejora de las pruebas de diagnóstico clínico y la estratificación de pacientes, así como para el diseño de herramientas tratagnósticas.

Objetivo

Rare inherited kidney diseases (RIKDs) encompass over 150 different conditions. They often lead to patients requiring renal replacement therapy being a major cause of end stage renal disease, severely compromising the patients’ quality of life and posing a high financial burden in healthcare. They are characterised by a high degree of phenotypic heterogeneity and by the absence of biomarkers for disease diagnosis, prognosis and inadequate therapeutic management. The main aim of the proposed work is to develop new disease ontology for three RIKDs (Thin Basement Membrane nephropathy, CFHR5 nephropathy and MUC1 kidney disease) using a deep-phenotyping approach. Phenotypic and genetic data will be integrated for biomarker discovery and to provide new knowledge for the development of a novel theranostic tool. Whole exome sequencing (WES) of cases and controls is currently underway at the host for the identification of relevant genetic variants. Using a dual biofluid-dual platform approach to maximise metabolome coverage, the metabolic profiles of healthy individuals will be compared to those of RIKD patients to identify disease-specific metabolic markers. Rigorous data analysis methodologies will be employed to integrate WES, metabolomic and clinical data for the identification of robust composite genotype-phenotype signatures of the diseases. These will elucidate molecular disease pathomechanisms, enabling better clinical diagnostics and improved patient stratification. The proposed work will provide a vital genotype-phenotype framework from which future theranostic tools can be more precisely designed and evaluated, towards precision medicine. The proposed research and training program will complement the applicant’s skills in metabolomics and systems biology with the host’s expertise in genomics and molecular diagnostics to enhance her professional maturity and facilitate new international research and innovation initiatives and multidisciplinary collaborations.