Grant: CIHR Fellowship

Mechanotransduction consists of sensing and transforming physical tensions on the cell membrane into intracellular signals. Piezo1 and Piezo2 are mechanically-activated ion channels that play crucial roles in sensory transduction as well as cardiovascular and developmental regulation. In the central nervous system (CNS), Piezos haven't been reported. My preliminary data reveal Piezo1 responses in microglia, known as the resident macrophages of the CNS. These highly dynamic cells maintain CNS homeostasis, respond to damage and invading pathogens, and underlie many neurodevelopmental and neurodegenerative diseases. Piezo1 may be essential in regulating mechanosensitive processes that characterize microglial function under resting and pathological states. Therefore, we sought to validate the functional expression of Piezo1 in microglia, identify the physiological mechanisms affected by Piezo1, and test the behavioral effects of Piezo1 loss- and gain-of-function in the appropriate animal models. My preliminary results show Piezo1-mediated calcium signals in cultured microglia, a response that is greatly up-regulated in activated microglia. This suggests an important role of Piezo1 in mechanosensitive phenomena that occur under activation, such as morphological alterations, migration, and phagocytosis. The relevance of Piezo1 in these processes will be investigated in vitro and in vivo by comparing control mice to Piezo1 loss- or gain-of-function transgenic models. Once a Piezo1-dependent process is identified, the appropriate mouse disease model will be tested to check for behavioral phenotypes and gain insights on the clinical relevance of microglial Piezo1. This work would present the first evidence of the presence of Piezos in the CNS and may reveal critical roles of mechanotransduction in microglial function underlying neurodevelopmental and neurodegenerative diseases.