Our body is made of trillions of cells, that share the same DNA blueprint but are specialized to perform different tasks. As in a society made of multiple individuals, our cells need to constantly exchange information to coordinate their activities, while being aware of their surroundings at all times. But how does a cell detect and process information from the external world? Dr. Francesco Tombola, Assistant Professor of Physiology & Biophysics at University of California, Irvine, addresses this fundamental question, focusing on molecular events that happen at the plasma membrane, the interface between the "inside" and the "outside" of the cell. Understanding how cells in our body receive and process information from their surroundings through the activation of membrane proteins known as ion channels will provide new pharmacological targets for treating many diseases, including cancer, stroke, autoimmunity, and autism spectrum disorders.

Membrane proteins, or ion channels, allow ions to enter or exit the cell when properly activated by a stimulus. The movement of ions then triggers important biological processes such as muscle contraction, hormone release, cellular proliferation, migration, or differentiation. Malfunctioning ion channels can thus render a cell unable to detect external signals, or cause the cell to respond to signals in the wrong way, for example by proliferating excessively, by migrating to the wrong location, or by shutting down defenses against invading pathogens. In collaboration with prominent researchers like Drs. Medha Pathak and Lisa Flanagan at UC Irvine and with the Center for Autism Research and Translation, Dr. Tombola and his team are currently investigating two ion channels that respond to physical cues: the Hv1 channel, which is activated by electrical signals, and the Piezo1 channel, which is activated by mechanical stretch of the membrane. Ultimately, Dr. Tombola hopes to bring to the table the unique perspective on ion channels and the interdisciplinary approach, to identify new therapeutic targets that may be overlooked by more traditional approaches.

Current research includes:

• Anticancer Drug Development Targeting Hv1 Channel: Hv1 proteins serve many critical functions like regulating the activity of enzymes that help facilitate our immune response and boosting sperm cell motility. However, enhanced Hv1 activity correlates with lower survival in patients with several types of cancer, such as B-cell malignancies, and breast and colorectal cancers. Excessive Hv1 activity also increases the metastatic potential of cancer cells, and in the brain, Hv1 is found to worsen brain damage in an animal model of ischemic stroke. Therefore, Dr. Tombola and his team are currently studying how the Hv1 channels work at the molecular level, to develop Hv1 inhibitors for applications as anticancer drugs and as neuroprotective agents by bringing down the concentration of Hv1 proteins where they are over-expressed. In the next two years, he hopes to identify these Hv1 inhibitors and to begin testing their efficacy and potential side effects in animal models.
   
• Neural Stem Cell Transplant Therapy: The irreversible loss of neurons is a common problem in neurodegenerative diseases. Stem cell therapy aims at replenishing lost neurons by transplanting stem cells. The ability of these cells to generate neurons after transplant is key to successful treatment. Piezo1 channel plays a key role in converting mechanical force into biological signals in a variety of cell types, and in collaboration with Dr. Medha Pathak and Dr. Lisa Flanagan at UC Irvine, Dr. Tombola and team have recently found that neural stem cells rely on Piezo1 activity to interpret mechanical cues from the surrounding environment and to decide whether to differentiate into neurons or astrocytes. Currently, the team is investigating whether Piezo1 can be used as a pharmacological target to improve the outcome of stem cell transplant therapy.
   
• New Diagnostic Tools for Autism Spectrum Disorder (ASD): Rapid and accurate screening to diagnose children with ASD is critical, since enrollment in early intervention programs can improve outcomes. As part of the UCI Center for Autism Research and Translation (CART), the Tombola and Flanagan labs are working to develop new cell-based diagnostics for ASD, and are currently testing two complementary electrophysiological measures to determine whether they distinguish ASD and control cells through resources available at CART's core services. In the next few years, Dr. Tombola hopes to accomplish proof-of-concept assessment of this diagnostic approach for early detection of ASDs.