Project Details
Projekt
Genetic variants of the mechanosensitive ion channel Piezo1 in red blood cells - their role in human physiology and evolution
Applicant
Professor Dr. Lars Kaestner
Subject Area
Anatomy and Physiology
Evolution, Anthropology
Hematology, Oncology
Evolution, Anthropology
Hematology, Oncology
Term
since 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 522062907
This project aims to establish the possible links between erythroid Piezo1 polymorphisms and channel activity, deformability, oxygen carrying capacity of red blood cells (RBC), and finally tissue oxygenation. Reaching this aim will support or disapprove the hypothesis of the possible role of Piezo1 variants in adaptation to the changing environmental conditions and natural selection in modern humans (mh). To test our hypothesis, we aim to perform genome editing of human-induced pluripotent stem cells (iPSC) carrying the mh_Piezo1 sequence (coding 307G) and replace it with the archaic arc_Piezo1 variant (coding 307S). Ex vivo amplification of RBC from modified iPSC (arc_RBC) will allow us to investigate the electrophysiological arc_Piezo1 channel properties and its impact on erythropoiesis and, finally, RBC function in comparison to the unmodified RBC (mh_RBC). Furthermore, in vivo effects on RBC properties, oxygen delivery, and tissue oxygenation caused by Piezo1 alterations will be investigated systemically in a mouse model with genetically or pharmacologically modified Piezo1 activity. We will use a gain of function (GOF) mouse model. To get initial insight into the role of Piezo1 variants in human tissue oxygenation, Piezo1 channel function and RBC properties as well as tissue oxygenation measurements after physical exercise will be performed in a small cohorts of Hereditary Xerocytosis (HX) patients carrying known Piezo1 GOF mutations. We do not aim to investigate the pathophysiology of HX, but we will take advantage of the pathological Piezo1 mutations and their effect on tissue oxygenation under stress conditions in vivo. Comparable experiments will be performed in a matched group of healthy controls. Finally, mathematical modelling of potential environmental determinants and associated selective processes is a viable approach to distinguish demographic from selective effects, in our case, to elucidate the demographic landscape and history of Piezo1 polymorphisms affecting RBC physiology (channel function, Calcium signalling, cell flow properties, and oxygen delivery capacity). Various methods have been proposed for estimations from binary or ordinal genotypic/phenotypic data from a limited number of individuals, including Approximate Bayesian Computation (ABC) methods. We will use the latter to test our two hypotheses by simulating the effects of potential selection mechanisms based on our experimental results.
DFG Programme
Research Grants
International Connection
Austria, Netherlands, Switzerland
Partner Organisation
Schweizerischer Nationalfonds (SNF)
