Interstitial Cells of Cajal

Although motility disorders affect millions of people, the underlying pathophysiology of these disorders has long been unclear. Dr. Farrugia's research team has studied the cellular basis of motility diseases for more than 20 years. In 2000, the lab published the first study showing that loss of interstitial cells of Cajal (ICC) is the main defect in slow-transit constipation. Since then, the team has shown that ICC defects are present in intestinal pseudo-obstruction and gastroparesis.

Coordinated electrical activity in the gastrointestinal tract requires the interaction of several cell types, including nerves, interstitial cells of Cajal and smooth muscle cells. Interstitial cells of Cajal generate the electrical slow wave that drives regular smooth muscle contractility.

Over a series of more than 20 manuscripts, the Cellular and Molecular Physiology of Gastrointestinal Disorders Laboratory has combined electron microscopy and light microscopy to show that more than 95% of people with gastroparesis have abnormalities in interstitial cells of Cajal. The lab also showed that when the deficit in interstitial cells of Cajal is corrected in animal models, normal gastric emptying is restored. Now the lab is focused on discovering new targets and therapies to treat gastroparesis.

The lab has identified how defects in ion channels expressed in interstitial cells of Cajal, such as ANO1, SLC4A4 (NBCe1) and NaV1.5, lead to abnormal function and disease. The lab also is investigating the molecular mechanisms for pacemaker generation in some but not all subtypes of interstitial cells of Cajal. The lab has shown the importance of the calcium-activated chloride channel ANO1 in the regulation of coordinated gastrointestinal smooth muscle function and the transcriptional regulation of ANO1 by Gli1 and Gli2.

The lab also reported the selective expression of the electrogenic Na+/HCO3− cotransporter SLC4A4 in pacemaker ICC and described its role in SW amplitude and frequency regulation. The lab is investigating how the calcium-activated chloride channel ANO1, acting with the sodium bicarbonate co-transporter SLC4A4/NBCe1, regulates calcium transients in ICC that in turn regulate contractile activity. Using state-of-the-art epigenomic and traditional approaches, the interactions between ANO1, the sodium bicarbonate transporter SLC4A4/NBCe1, ICC and gastrointestinal disease are being investigated by both in vitro and in vivo models.

Dr. Farrugia's lab also has showed that NaV1.5, a voltage-gated sodium channel, is expressed in the human gut and that this voltage-gated ion channel is mechanosensitive. The lab's subsequent work dissected the mechanism of NaV1.5 mechanosensitivity at the molecular level and the relevance of NaV1.5 mechanosensitivity in gastrointestinal physiology and pathophysiology.

Read more about the Cellular and Molecular Physiology of Gastrointestinal Disorders Laboratory's research on mechanosensitive ion channels.