Mechanisms, cardio-metabolic consequences, and treatment strategies for high- altitude excessive ertythrocytosis and Chronic Mountain Sickness in the Andes. (360G-Wellcome-107544_Z_15_Z)

Chronic Mountain Sickness (CMS) is a highly prevalent clinical syndrome in Andean and other high-altitude populations. Its main sign is excessive erythrocytosis (EE) which is associated to severe hypoxemia and neurological symptoms such as headaches, fatigue, somnolence, and alterations of sleep and memory. Given its incapacitating characteristics, CMS prevents afflicted individuals from having a normal occupational and social life. The pathophysiological mechanism of EE and CMS is still debata ble; however, hypoxemia represents the underlying stimulus as relocation of CMS patients to sea-level reverts the disorder completely. Evidence indicates that CMS symptomatology is a consequence of EE given that hemodilution at the altitude of residence alleviates the CMS-related symptoms. We have made important progress with novel findings on the pathophysiology of EE and CMS as we have recently identified a mechanism that increases the availability of erythropoietin (Epo) through its soluble receptor (sEpoR). The aims of the present project are: i) to investigate whether differential expression of the sEpoR and its membrane counterpart is associated to increased sensitivity to Epo; ii) to evaluate the cardio-metabolic consequences of EE, and iii) to explore three novel treatment strategies; two non-pharmacological in CMS highlanders, and one pharmacological in an murine model of altitude-induced erythrocytosis.