Descrizione del progetto
Genetica del metabolismo in alta quota
Sebbene la genetica sia associata con l’adattamento alle alte quote nelle popolazioni native di questo ambiente, i legami con i processi molecolari e fisiologici relativi alla funzione metabolica rimangono ampiamente sconosciuti. È interessante notare come una porzione significativa degli abitanti dell’altopiano delle Ande sviluppi il mal di montagna cronico, caratterizzato da una maggiore eritrocitosi e da una disregolazione cardiometabolica. Il progetto Champagne, finanziato dall’UE, impiegherà genotipizzazione, sequenziamento dell’RNA, test cardiopolmonari, metabolomica, lipidomica e analisi mitocondriali per studiare gli abitanti andini di alta quota per identificare le differenze alla base di (pato)fisiologie (dis)adattive. Questo progetto multidisciplinare esplorerà i legami tra il polimorfismo genetico adattivo e i meccanismi di protezione contro lo stress ipossico.
Obiettivo
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.
Campo scientifico
Parole chiave
Programma(i)
Argomento(i)
Meccanismo di finanziamento
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinatore
CB2 1TN Cambridge
Regno Unito