Descripción del proyecto
Genética del metabolismo a altitudes elevadas
Si bien las características genéticas se asocian con la adaptación a la altitud elevada en poblaciones nativas de estos entornos, todavía se desconocen en gran medida los vínculos con procesos moleculares y fisiológicos relacionados con la función metabólica. Cabe destacar que una parte significativa de los habitantes de las montañas andinas desarrolla un mal de montaña crónico caracterizado por el aumento de la eritrocitosis y la desregulación cardiometabólica. El proyecto financiado con fondos europeos Champagne utilizará técnicas de genotipado, secuenciación de ARN, ensayos cardiopulmonares, metabolómica, lipidómica y análisis mitocondriales para estudiar poblaciones andinas que habitan en altitudes elevadas, con el fin de identificar las diferencias subyacentes en la fisio(pato)logía (mal)adaptativa. Este proyecto pluridisciplinario analizará los vínculos entre los polimorfismos genéticos adaptativos y los mecanismos de protección frente al estrés hipóxico.
Objetivo
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.
Ámbito científico
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Régimen de financiación
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinador
CB2 1TN Cambridge
Reino Unido