[SCItalk] Biomodulation of Anion Channels: The Next Frontier in the Treatment of Airway Diseases, Neuropathies, and Cancer
Washington University in St. Louis, MO, USA
Calcium-activated chloride channels (CaCCs), such as those of the TMEM16/Anoctamin family, and CaCC regulator (CLCA) proteins are strongly emerging as both biomarkers and promising therapeutic targets for variety of conditions, in particular, but not exclusively, inflammatory airway diseases such as asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF). We discovered that secreted CLCA1 strongly and selectively potentiates TMEM16A activity by engaging the channel at the cell surface and preventing its reinternalization, and in this seminar, I will outline the scientific milestones that led to our current working model of CLCA1-TMEM16A molecular interactions. I will share exciting new data showcasing the promise of CLCA1-derived biologics for the restoration of anion conductances in airways of CF patients independently of the mutant CFTR genotype; and I will discuss the potential of TMEM16-CLCA partnerships for the treatment of other pathologies, including neurologic disorders and cancer.
I earned my PhD in 2003 from the University of Barcelona, under the guidance and mentorship of Joana Maria Planas from the School of Pharmacy Physiology Department; soon after graduating, I joined the team of Ernie Wright at the University of California, Los Angeles Department of Physiology for postdoctoral training. A member of the research track faculty at the Washington University School of Medicine in Saint Louis since 2009, first in the Department of Cell Biology and Physiology, and as of 2018 in the Department of Anesthesiology, I continue to pursue my passion for ion channel and solute transporter biophysics and pathophysiology, and for the mentoring of students and junior scientists.
Membrane transport proteins are responsible for communication and exchange between and within cells, and underlie phenomena so vital as nutrient and drug absorption, distribution and clearance; immune response, neurotransmission, and fluid and hormone secretion. For many such proteins, recent advances have only begun to tap their potential as drug targets and diagnostic tools, and a substantial gap in our knowledge remains regarding specificity and off-target interactions. My research is focused on ligand-gated ion channels, such as the TMEM16 chloride/bicarbonate channel family, the ATP-dependent potassium (KATP) and the big conductance potassium (BK) channel complexes; and on epithelial metabolite and drug transporters, in particular those of the SLC superfamily. Using a multidisciplinary approach which includes electrophysiology, kinetic modeling and in vivo imaging, I investigate the structure-function relationships, pharmacology and physiology of these proteins. My interest is double-pronged: on one hand, I wish to understand how alterations in their structure or regulation lead to pathologies. On the other hand, I take advantage of the biochemical and biophysical properties of these marvelous molecular machines to aid in the design and development of novel, specific drugs and diagnostic probes.
Host: Carles Solsona