Sodium/hydrogen exchangers (NHEs) are ion transporters catalysing the electroneutral exchange of sodium with protons in prokaryotes and eukaryotes. NHE1 is a ubiquitous mammalian plasma membrane transporter. In addition to the control of cell volume and cell pH, NHE1 regulates cell migration and mechanosensation, which in turn contribute significantly to the pathogenesis of cancer and cardiovascular diseases in humans.
Since the underlying molecular mechanisms of this regulation remain elusive, I have made use of a novel generation of yeast-two-hybrid assays and identified several putative regulators of NHE1. The aim of this proposal is to analyse these newly identified NHE1 interacting proteins in the context of NHE1 regulation with emphasis on cell migration and mechanosensation.
For this purpose, I will be combining biochemical and imaging studies for a detailed analysis of these protein interactions with the help of recently established fibroblast cell lines I created from NHE1 wild-type and knock-out mice. In-depth analysis on the impact on NHE1 activity regulation will be done by our new assay combining self-referencing ion-selective microelectrodes during whole-cell patch-clamp with concomitant pipette perfusion. Boyden chamber and wound healing scratch assays will be used to detect how NHE1 interacting proteins affect cell migration.
This multi-disciplinary approach will uncover molecular mechanisms of NHE1 regulation and inevitably shed light on how NHE1 influences the development of cancer and cardiovascular disease. I will conduct the project in the membrane biology group of Prof. Matthias Hediger at the Institute of Biochemistry in Bern, Switzerland.
This fellowship will allow me to acquire all the skills and expertise necessary to become an independent researcher. Having a strong background in Basic Science and Medicine, I am convinced to be able to contribute significantly to the promotion of an original and sustainable ion transport research in Europe.
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