Multi-Scale Systems Analysis of Cell-Cell Communication Networks in Inflammation
Schematic illustration of the highly-prevalent and debilitating complex women’s reproductive disesase endometriosis, showing some of the multiple immune cell types involved along with some of their cell-cell communication molecules and their potential influences on peritoneal fluid organ sites due to proliferation and invasion of tissue cells refluxed from the uterus during the menstrual cycle. This is one of the major applications that we are developing multi-scale computational models for, in order to predict useful targets for therapeutic intervention. (From Tariverdian, Seminars in Immunopathology [2007].)
Endometriosis is a chronic disease characterized by growth of the endometrial lining outside of the uterus, causing inflammatory lesions on the intestines, bladder, ovaries, and other internal organs. Symptoms of debilitating pain often appear in the teenage years and progress, such that surgery is needed to remove the tissue, which can invade deeply into underlying organs. Inflammatory bowel disease is characterized by lesions of inflammation on the bowel, causing debilitating pain and disruption of normal bowel function. Both diseases involve disorders of immune behavior interacting with epithelial tissues. In this project, we are developing a general approach to investigate communication networks among immune cells and tissue cells, using a combination of experimental and computational tools to study patient samples and animal models representing facets of the disease. For example, we have found that a particular group of endometriosis patients has a “signature” set of molecules that indicate a particular immune cell, the macrophage, is active and driving inflammation and invasion. Further, we have found a way to inhibit the inflammatory behavior using exploratory new drugs that block intracellular signaling. Similarly, in inflammatory bowel disease, by examining interactions between immune cells and tissue cells, we found that the normal gut epithelial lining cells were recruiting a particular kind of immune cells to drive inflammation. Overall, by carrying out a comprehensive analysis of both intracellular and extracellular communication and signaling networks we are learning how to block the most dangerous of the inflammatory pathways, and how these various communication networks may be operating differently in different subsets of patients.
