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

RESEARCH INTEREST

The major focus of our work is on inflammatory bowel disease (IBD) and malignancy. In characterizing the gastrointestinal manifestations in several rare genetic disorders involving deficiencies of innate immune function, we made the observation that nearly a third of affected patients develop a clinical and pathologic syndrome indistinguishable from Crohn's disease. This suggests that defects in mucosal innate immune function may play a central and previously unappreciated role in the pathogenesis of Crohn's disease. Furthermore, this association largely disappeared in the United States after 1991, when G- and GM-CSF became available and were nearly universally applied to patients with genetic disorders like GSD-1b. This suggested that the introduction of colony stimulating factors may have changed the natural course of disease, either delaying or preventing the development of intestinal inflammation. We also noted that a number of GSD-1b patients with a Crohn's-like phenotype had improvement or remission of their disease after initiating G- or GM-CSF. 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 Crohn's Disease. Results to date have demonstrated a rapid clinical response for both mucosal and fistulizing Crohn's Disease. This work is currently in phase III trials across the United States and Europe. Our ongoing focus is on better defining the molecular mechanism(s) responsible for this clinical efficacy, both in animal models and translational investigations associated with the ongoing clinical trials.

A second area of interest is the biology of the Regenerating (REG) gene family. My laboratory is involved in the study of the cellular signaling pathways and mediators used to sense and respond to epithelial injury. Strategies for investigating the gene programs activated by colonic epithelial injury using high density DNA arrays have shown that the REG family is an important mediator of tissue repair programs that are activated following mucosal injury. Members of the REG gene family are among the most highly up-regulated genes in ulcerative colitis or Crohn's disease. The REG gene products and their receptor(s) constitute an entirely new receptor-ligand class. REG proteins have both pro-mitogenic and anti-apoptotic properties. Dysregulated expression is also an early step in the development of malignancy throughout the gastrointestinal tract and represents an exciting new therapeutic target in gastric, colorectal, pancreatic and prostate adenocarcinoma. Strategies designed to interrupt this autocrine/paracrine signaling pathway are currently being tested.

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