Brian K. Dieckgraefe, M.D., Ph.D.

DEPARTMENT OF Internal Medicine
Keywords: Crohn's disease, mucosal immunity, neutrophils, ulcerative colitis

Most of the diseases that affect the gastrointestinal tract involve damage to the epithelial barrier. In the intestine, epithelial cells serve as an important host barrier to toxic or microbial constituents in the lumen. A major focus of my laboratory has been the study of the cellular signaling pathways and mediators used to sense and respond to epithelial injury. Like epithelial cells in other locations, the colonic or small bowel epithelium must respond to focal injury with a genetically programmed repertoire of adaptations. Very little is known about the scale of this response or the signaling pathways that mediate this transcriptional program. Strategies for investigating the gene programs activated by colonic epithelial injury employ the use of high-density DNA arrays to identify genes induced by injury, as well as potential mediators of tissue repair programs. One example is the REG (regenerating) family of proteins. These proteins are not normally expressed in the colonic epithelium, but are markedly up-regulated in ulcerative colitis or Crohn's disease. The biological and clinicopathological roles for the REG family proteins are poorly understood. However, their expression is tightly linked with tissue repair and regeneration. Our strategy for defining the role for this gene family is to completely characterize the expression of the REG family in colonic injury, to investigate the functional role for these proteins by examining the interaction with other proteins expressed in colonic epithelium, and to identify and further characterize the novel cell-surface receptor for members of this gene family. Our work to date has demonstrated that REG gene products and their receptor constitute an entirely new receptor-ligand class and are leading candidates for initiating tissue regenerative programs following mucosal injury in the gastrointestinal tract.

A second interest of my lab has been the identification of proximate events in the development of Crohn's disease (CD). A major hurdle has been the identification of these preclinical abnormalities, since patients may not manifest symptoms prior to disease onset. We have approached this dilemma from a different standpoint. Specifically, patients with certain immunodeficiency syndromes appeared to hold clues to the initial events in the pathogenesis of CD. We have identified and characterized the gastrointestinal manifestations in several rare genetic disorders involving deficiencies of neutrophil function. Nearly one-third of affected patients develop a clinical and pathologic syndrome indistinguishable from CD. This suggests that defects in mucosal neutrophil function may play a central and previously unappreciated role in CD. Additionally, several reports have described remission of the Crohn's phenotype when hematopoietic colony-stimulating factors were given for infection prophylaxis. As a result of these findings, we undertook investigator-initiated studies of agents designed to stimulate innate immunity in patients with moderate to severely active CD. Results to date have demonstrated a rapid clinical response for both mucosal and fistulizing CD. We have recently begun to focus on defining the molecular mechanism(s) responsible for this impressive clinical efficacy.

Both of the projects outlined above will contribute to our understanding of mucosal gene expression induced by injury and advance our understanding of diseases characterized by chronic epithelial damage.