I have been studying and working in Professor Andrea Yool's Aquaporin Physiology & Drug Discovery Lab in the past 7 years. The water channels known as aquaporins (AQPs) are an ancient family found in all the kingdoms of life, from bacteria and plants to invertebrates and vertebrates, and play key roles in water balance and fluid homeostasis across cell membranes. The thirteen classes of human AQPs show tissue-specific patterns of expression relevant for health and pathophysiological processes. Our goals are to define the molecular basis of the dual water and ion channel function of aquaporins, to understand the roles of AQPs in physiological systems, and to build a definitive portfolio of AQP antagonist and agonist compounds as tools for basic research and clinical innovation. Aquaporins are currently being uncovered as essential components of rapid cell migration in wound healing and cancer metastasis, particularly in aggressive cancers such as glioblastoma and colon cancers. We have shown molecular knockdown or pharmacological blockade of AQP1 can slow or stop aggressive cancer cell movement. Our work over the past decade has challenged the original dogma that the archetypal channel AQP1 is rigid and constitutively open. We have shown that AQP1 is regulated by intracellular signals and serves as cGMP-gated ion channel as well as an osmotic water channel. Our focus on AQP pharmacology defined the first library of pharmacological agents in the world, based on arylsulfonamide scaffolds showing differential activities on the ion and the water pores. We are now testing potentially powerful dual therapies for blocking cell migration. We are also defining pharmacological AQP modulators from traditional Chinese and Indian medicinal herbs, identifying the active chemical components and their molecular targets of action on AQP gating domains. Our findings offer exciting translational opportunities for clinical intervention in cancer metastasis, brain oedema, hydrocephalus, and other fluid transport disorders. Our drug agents are currently being tested in vivo in collaborative projects in Australia, Europe and the USA.
In the past year, through the collaboration with Dr. Sabrina Heng from Center for Nanoscale BioPhotonics (CNBP), we have developed a novel ion sensor (SHL) that has high affinity to Li+ ion. With the help of SHL, we successfully imaged the ion entry through AQP1 cation channel for the first time. This novel Lithium sensor together with other ion specific analogs are valuable research tools to study the function of various ion channels non-invasively, especially in a more fragile system.
Kourghi, M., Pei, J., De Ieso, M., Nourmohammadi, S., Chow, P., & Yool, A. (2018). Fundamental structural and functional properties of Aquaporin ion channels found across the kingdoms of life. Clinical and Experimental Pharmacology and Physiology, OnlinePubl(4), 401-409. DOIScopus1
Palethorpe, H., Tomita, Y., Smith, E., Pei, J., Townsend, A., Price, T., . . . Hardingham, J. (2018). The aquaporin 1 inhibitor bacopaside II reduces endothelial cell migration and tubulogenesis and induces apoptosis. International Journal of Molecular Sciences, 19(3), 1-10. DOI
Kourghi, M., Pei, J., De Ieso, M., Flynn, G., & Yool, A. (2016). Bumetanide derivatives AqB007 and AqB011 selectively block the aquaporin-1 ion channel conductance and slow cancer cell migration. Molecular Pharmacology, 89(1), 133-140. DOIScopus8WoS8Europe PMC7
Pei, J., Ameliorate, J. L., Kourghi, M., De Ieso, M., & Yool, A. (2016). Drug Discovery and Therapeutic Targets for Pharmacological Modulators of Aquaporin Channels. In G. Soveral, S. Nielsen, & A. Casini (Eds.), Aquaporins in Health and Disease: New Molecular Targets for Drug Discovery (pp. 273-296). Boca Raton, FL: CRC Press.
Pei, J. V., Heng, S., De Ieso, M., Sylvia, G., Kourghi, M., Abell, A. D., & Yool, A. J. (2018). Real-Time Imaging of Lithium 'Hot-Spots': An Analysis of Ion Conductance in Aquaporin-1 using Novel Photo-Switchable Sensor. Poster session presented at the meeting of BIOPHYSICAL JOURNAL. San Francisco, CA: CELL PRESS.
Pei, J., Campbell, E., & Yool, A. (2013). Inhibition of aquaporin-1 but not aquaporin-4 water permeability by bacopaside I derived from Bacopa monnieri. Poster session presented at the meeting of PLANTA MEDICA. GEORG THIEME VERLAG KG.
Participated and experimental results lead to the successful application of the following grant.
Project Title / No.
Characterisation of aquaporin-1 (AQP1) ion channel activity in migrating cancer cells using a novel photoswitchable fluorescent probe