Ultrasound has been widely used for diagnostic imaging owing to its acoustic wave, which can be non-invasively delivered into deep tissues in a focused manner. The global market of medical ultrasound is estimated to reach 6 billion USD by the year 2021. Human tissues are mostly insensitive to ultrasound illumination, making it extremely safe to conduct diagnostic imaging without inducing unnecessary side effects to illuminated regions. However, this advantage can be turned into a drawback if one uses ultrasound to manipulate cellular activities for therapeutic purposes. To circumvent this long term technical limitation and extending the toolkit of medical ultrasound, we attempt to establish sonogenetic approaches to control cellular activities using medical ultrasound excitation. One strategy we make use of is the identification of the ultrasound-responsive proteins from mother nature. We recently focused on the membrane protein Prestin, which resides in the mammalian auditory systems and is essential for high-frequency hearing. Heterogeneous expression of the engineered prestin has allowed mammalian cells to sense ultrasound stimulation, which evoked a calcium influx from the extracellular space into their cytosol under a low-frequency and low-pressure ultrasound condition. Owing to the excellent penetration depth of low-frequency ultrasound (~150 millimeters in depth), our sonogenetic tool will serve as new strategies for non-invasive cell therapy in the deep tissue of large animals like primates. Based on these promising discoveries, we aim to explore the Prestin variants that are more sensitive to ultrasound by random mutagenesis or analyzing Prestins from echolocating species. The high-ultrasound sensitive Prestin variants will be utilized to develop different sonogenetic tools for remotely controlling gene expression, blood glucose homeostasis, neuronal cell activities, and immune cell activities in vitro and in vivo. The results obtained in our proposal will uncover the molecular mechanisms of how echolocating species sense ultrasound. The series of sonogenetic approaches developed here will be applicable to manipulate cellular activities for various therapeutic purposes non-invasively and significantly impact the global ultrasound market soon