Lyna Luo, PhD, Associate Professor of Biotechnology and Pharmaceutical Sciences (COP), and Jerome Lacroix, PhD, Associate Professor of Biomedical Sciences (COMP) have been awarded a total of $1,476,258 for their multi-PI NIH R01 renewal entitled, “Pharmacological modulation of mechanosensitive Piezo ion channels.” This is the renewal of two PIs’ previous NIH R01 received in 2019.
The transduction of mechanical forces into biological signals is vital for all living organisms. In vertebrates, this task is mainly performed by mechanosensitive membrane proteins called PIEZO1 and PIEZO2. These proteins act as ion channels, producing an influx of sodium and calcium ions in response to mechanical deformations of the cell membrane. These proteins are associated with numerous pathologies including hypertension, red blood cell dehydration, lymphedema, arthrogryposis, inflammation, pain, and cancer. Selective modulation of these ion channels with small molecules could help better understand their physiological roles and perhaps treat some of their associated conditions. We have previously identified a pharmacological binding site located in a regulatory region of PIEZO1. In this proposal, we will investigate how the binding of a small molecule at this site cause conformational changes that promote PIEZO1 activation. We will next exploit this binding site to develop novel PIEZO1 modulators with improved pharmacological properties. Successful completion of this project will deepen our fundamental understanding of vertebrate mechanotransduction and uncover novel molecules with potential value for basic research and the clinic.