Description du projet
La génétique du métabolisme à haute altitude
Même si la génétique est associée à l’adaptation à l’altitude chez les populations indigènes de ce type d’environnements, les liens avec les processus physiologiques et moléculaires liés à la fonction métabolique restent largement inconnus. Il est intéressant de noter qu’un pourcentage considérable de personnes andines manifestent le mal chronique des montagnes, caractérisé par une érythrocytose accrue et un dysfonctionnement cardiométabolique. Le projet Champagne, financé par l’UE, utilisera le génotypage, le séquençage ARN, des examens cardiopulmonaires, ainsi que des analyses mitochondriales, lipidomiques et métabololiques, pour étudier les Andins de haute altitude en vue d’identifier les différences qui sous-tendent la (patho)physiologie des troubles de l’adaptation. Ce projet pluridisciplinaire examinera les liens entre le polymorphisme génétique adaptatif et les mécanismes de protection contre le stress hypoxique.
Objectif
High-altitude hypoxia is a known physiological stressor. Genetic signals associated with high-altitude adaptation have been identified in populations native to this environment, yet the links to molecular/physiological processes affording protection against hypoxic stress, specifically those related to metabolic function, remain largely unknown. Conversely, a significant proportion of Andean highlanders develop chronic mountain sickness (CMS), characterised by excessive erythrocytosis and cardiometabolic dysregulation.
I will combine genotype analysis, RNA sequencing, cardiopulmonary exercise testing, metabolic/lipidomic profiling and mitochondrial function analyses to study high-altitude Andeans with and without excessive erythrocytosis, in order to identify underlying differences in (mal)adaptive (patho)physiology. Applying methods developed by the partner host laboratory, I will examine pre-selected candidate gene variants along with skeletal muscle metabolic phenotype, probed through assessment of mitochondrial capacity for substrate metabolism. Metabolomic/lipidomic analysis of muscle and plasma alongside measures of whole-body exercise performance will demonstrate the impact of these functional changes in vivo.
This multidisciplinary approach will explore the links between adaptive genetic polymorphisms and molecular/physiological processes affording protection against hypoxic stress. It has the potential to further our understanding of the individual metabolic responses to hypoxia by distinguishing healthy adaptive signals from disease-related signatures, and link genetic, metabolic and whole-body physiological function data in the context of CMS. It will provide a foundation for addressing fundamental questions concerning human evolution whilst improving our understanding of highly prevalent hypoxia-related conditions and the metabolic aetiology of these.
Champ scientifique
Mots‑clés
Programme(s)
Régime de financement
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinateur
CB2 1TN Cambridge
Royaume-Uni