Project description
Genetics of the high altitude metabolism
While genetics are associated with high-altitude adaptation in populations native to this environment, the links to molecular and physiological processes related to metabolic function remain largely unknown. It is interesting to note that a significant proportion of Andean highlanders develop chronic mountain sickness characterised by increased erythrocytosis and cardiometabolic dysregulation. The EU-funded Champagne project will employ genotyping, RNA sequencing, cardiopulmonary testing, metabolomics, lipidomics and mitochondrial analyses to study high-altitude Andeans to identify underlying differences in (mal)adaptive (patho)physiology. This multidisciplinary project will explore the links between adaptive genetic polymorphism and mechanisms of protection against hypoxic stress.
Objective
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.
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Funding Scheme
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinator
CB2 1TN Cambridge
United Kingdom