The research in my laboratory investigates the control of immune responses and how alterations in these responses contribute to the development of inflammatory bowel disease. In particular, our focus is on the mechanisms of activation and regulation of inflammatory signaling by the bacterial sensor protein Nod2 in immune cells and the gut.
An essential part of staying healthy is the ability of the body to sense and respond to infection. To do this, we have developed an immune system with specific sensors of bacteria, viruses, and other microorganisms on the surface and inside specific cells. One such sensor is a protein called Nod2, which plays an important role in detecting bacteria and telling the immune system to attack. Some people have mutations in Nod2 that change the way it functions, resulting either in turning this response “on” or “off” all the time. These changes in function not only affect the sensing of and response to bacterial infections, but also contribute to the development of specific auto-inflammatory diseases. One of these diseases is the inflammatory bowel disease, Crohn’s disease.
Crohn’s disease is a chronic and debilitating disease that affects approximately one million individuals in the United States. It is characterized by inflammation of the gastrointestinal tract, primarily in the small intestine. The cause of Crohn’s disease is unknown; however, it is clear that altered immune responses to bacteria are involved in disease susceptibility and pathogenesis. Disease symptoms include abdominal cramps and pain, persistent diarrhea, fever, and sometimes rectal bleeding. This disease can lead to loss of appetite and weight loss, fatigue, anal tears, and formation of fistulas or connections between the loops of the bowel and/or other internal organs.
Symptoms of the disease are periodic and will flare up causing active disease for a period of time, followed by times where the symptoms decrease or disappear. Crohn’s disease can occur at any age, but commonly affects both men and women equally between the ages of 15 and 35. It has been found that this disease tends to run in families, where 20-25% of all Crohn’s patients have other family members with the disease or a related inflammatory bowel disease. Genetic analysis of Crohn’s disease patients and their families identified several potential genes associated with an increased susceptibility to develop Crohn’s disease. The first gene conclusively identified with increased susceptibility to Crohn’s disease is Nod2. Individuals with Crohn’s disease were found to have specific mutations of Nod2 twice as frequently as unaffected individuals. These mutations of Nod2 result in an inability to recognize bacteria, indicating that proper activation of Nod2-dependent responses is essential for prevention of inflammatory bowel disease.
The goal of our research is to better understand the mechanisms involved in the development of Crohn’s disease to allow for more effective and personalized treatments of this debilitating disease. In particular, the laboratory focuses on the mechanisms of activation and regulation of inflammatory signaling by Nod2 in immune cells and the gut. To do this, we use a combination of molecular, biochemical, genetic, and cellular approaches to investigate these mechanisms to better understand the normal activation and control of Nod2 and how this is altered in Crohn’s disease.
In addition, recent genetic studies have implicated 30 more genes in Crohn’s disease susceptibility. We are also performing studies to identigy how some of these genes my function together in critical immune response pathways that are altered in Crohn’s disease. These studies will potentially identify additional, novel targets for treatment of Crohn’s disease.
Special thanks to the following individuals for their monetary support of our research program: