SUMMARY
Gianrico Farrugia, M.D., runs a National Institute of Health (NIH)-funded translational laboratory focusing on the enteric neurosciences. The laboratory is part of the Enteric Neuroscience Program at Mayo Clinic, of which Dr. Farrugia is director. His laboratory studies gastrointestinal smooth muscle, pacemaker cells of the gastrointestinal tract known as interstitial cells of Cajal, and enteric nerves.
The aim of Dr. Farrugia's work is to understand at a cellular, subcellular and molecular level how the normal functions of the gastrointestinal tract determine the defects that result in diseases such as diabetic gastroparesis, slow transit constipation and irritable bowel syndrome. Dr. Farrugia hopes to develop new strategies to treat these diseases by developing targeted disease-modifying agents, by using a variety of state-of-the-art techniques, including high-resolution imaging, ion channel activity recording and next-generation sequencing, and by creating cellular and tissue models of disease.
Focus areas
- The role of ion channels in the human gastrointestinal tract. Over the past 20 years, Dr. Farrugia's laboratory has produced the significant majority of all the published work on the type and distributions of ion channels expressed in human gastrointestinal cells and interstitial cells of Cajal. The lab's initial work focused on potassium channels expressed in human gastrointestinal smooth muscle cells and interstitial cells of Cajal, followed by calcium channels, and then the first description of sodium channels in these cell types. The laboratory has more recently reported on the chloride channel Ano1 in the human gut. In the past years, the laboratory has begun to understand the molecular mechanisms that give rise to electrical abnormalities that then result in abnormal smooth muscle contractility. The laboratory has linked functional variants and mutations to diseases such as gastroparesis and pseudo-obstruction. The laboratory has also identified that 2 to 3 percent of patients with irritable bowel syndrome have mutations in the sodium channel NaV1.5 and that targeting the defect can treat irritable bowel syndrome.
- Diabetic gastroparesis. Diabetic gastroparesis can occur in both type 1 and type 2 diabetes and result in significant morbidity, often in young to middle-aged women. Dr. Farrugia's laboratory seeks to determine the cellular and molecular basis of diabetic gastroparesis. The laboratory has shown that the major cellular defect in diabetic gastroparesis is a loss of a cell type known as the interstitial cells of Cajal. Other cell types, including neurons, also are affected. The laboratory has also shown that preceding loss of interstitial cells of Cajal is loss of an enzyme called heme oxygenase 1 that is produced in a type of macrophage known as an M2 macrophage. Restoring either the M2 macrophage or the products on the M2 macrophage by both the pharmacological and genetic mechanisms can completely reverse diabetic gastroparesis. The laboratory is now collaborating with others in the enteric neuroscience field to develop ways to treat human diabetic gastroparesis by targeting this pathway.
- The role of interstitial cells of Cajal in disease. Coordinated electrical activity in the tract requires the interaction of several cell types, including nerves, interstitial cells of Cajal and smooth muscle cells. Interstitial cells of Cajal generated the slow wave that drives regular smooth muscle contractility. The laboratory has played a leadership role in understanding that loss of interstitial cells of Cajal is the main defect in slow transit constipation and gastroparesis and is also present in intestinal pseudo-obstruction. The laboratory has also identified how defects in ion channels expressed in interstitial cells of Cajal such as Ano1 and NaV1.5 lead to abnormal function and disease.
- The role of carbon monoxide in the gastrointestinal tract. Dr. Farrugia's laboratory focuses on the gas carbon monoxide, showing that small levels of carbon monoxide produced by cells in the gastrointestinal tract are essential for the normal function of the gastrointestinal tract. Certain cell types release carbon monoxide, which then regulates the smooth muscle cells and the normal function of the gut. The laboratory has shown that induction of the enzyme producing carbon monoxide or delivery of inhaled carbon monoxide in diabetic models can reverse diseases such as delayed gastric emptying. The laboratory focuses on designing new ways to deliver carbon monoxide or heme oxygenase 1 is a therapy for diabetic gastroparesis and other nongastrointestinal disorders, including in the kidney.
Significance to patient care
The function of Dr. Farrugia's laboratory is to understand, on a molecular and cellular level, the mechanisms that result in normal gastrointestinal function and the defects that result in disease. Understanding these mechanisms is crucial for designing rational strategies to treat symptoms of disease, and for reversing the underlying defect. All work performed by Dr. Farrugia's lab has a goal to restore the gastrointestinal tract to normal function.
Professional highlights
- John H. Noseworthy, M.D., and Jay Alix Distinguished Chair, Mayo Clinic, 2019-present.
- American Neurogastroenterology and Motility Society:
- President, 2016-2017.
- President-elect, 2014-2016.
- Carlson and Nelson Endowed Executive Director, Center for Individualized Medicine, Mayo Clinic, 2013-2014.
- Basic science editor, Neurogastroenterology & Motility, 2011-2014.