Declan McCole, Ph.D.
Declan McCole, Ph.D., Assistant Professor

Delcan is an Associate Professor of Biomedical Sciences at the University of California, Riverside.

Delcan is an Associate Professor of Biomedical Sciences at the University of California, Riverside.

Research Summary

The intestinal epithelium is a single layer of cells that plays a critical role in human health. Intestinal epithelial cells are critical for the breakdown and uptake of nutrients, for absorption and secretion of electrolytes and water, regulation of immune function, communication with the intestinal microbiota and protection from pathogen infection. All of these features are critically dependent on an intact epithelial barrier. The main structural feature of the epithelial barrier that regulates epithelial permeability to electrolytes and macromolecules is known as the ‘Tight Junction’. This dynamic structure connects adjacent cells and is made up of transmembrane and regulatory proteins that can be modified by pathogens or inflammatory mediators to decrease or increase permeability.

Our lab uses a multidisciplinary approach to better understand the effects of inflammation on epithelial barrier function. We incorporate electrophysiology, molecular biology, biochemical and imaging approaches to better understand epithelial barrier and tight junction regulation in both in vitro and in vivo model systems. We also translate our studies to human disease using intestinal biopsies from human IBD patients. In addition, we are investigating novel treatments to restore barrier function.

Research Projects

1. Regulation of epithelial barrier function by the IBD candidate gene, PTPN2
The gene locus for the enzyme Protein tyrosine phosphatase non-receptor Type 2 (PTPN2), has been established as a candidate gene for both Crohn’s disease and ulcerative colitis in genome wide scan association studies (GWAS). It is also associated with two other inflammatory diseases, Celiac disease and Type I diabetes. Interestingly, all of these conditions are associated with an increase in intestinal permeability prior to evidence of inflammation. We identified that the PTPN2 gene and its protein product, T-cell protein Tyrosine Phosphatase (TCPTP), play a crucial role in restricting the capacity of the IBD-associated inflammatory cytokine, interferon-gamma (IFNγ) to induce barrier defects. Current studies are investigating PTPN2 regulation of barrier function using knockout mice and novel epithelial cell lines lacking PTPN2 or expressing mutated forms of PTPN2. Functional measures of the epithelial barrier as well as changes in expression and regulation of molecular targets in the tight junction are being studied. We are also exploring translational approaches to study PTPN2 regulation of barrier function in human patients.

2. Space Biology – The effect of microgravity on the epithelial barrier
Our group was one of only three labs nationally to secure a BioMed-ISS research grant funded by the initial cycle of a new collaborative program between NIH and NASA to conduct biomedical research on the International Space Station. This BioMed-ISS grant is a two-step process. In the current funding period (Phase I), we are conducting ground-based studies to assess the effects of a simulated microgravity environment on epithelial barrier function and tight junction proteins that regulate barrier function. The second three-year phase will involve development of novel technologies to facilitate functional assays of barrier function on the ISS, and performing an actual experiment in a zero-gravity environment on board the ISS.

3. Epithelial barrier and electrolyte transport regulation by the cellular energy sensor, AMPK
We previously identified that AMPK plays a partial role in IFNγ-induced barrier dysfunction through effects on the tight junction regulatory protein, zonula occludens-1 (ZO-1). Ongoing studies are focused on further elucidating how AMPK modifies tight junction regulation and its interactions with PTPN2, the IBD candidate gene that protects the epithelial barrier. In additional studies, we have identified that AMPK is involved in modifying electrolyte transport across colonic epithelial cells exposed to reactive oxygen species and we are now identifying molecular targets of AMPK involved in these events.

4. Development of novel treatments to restore barrier function
We have a number of ongoing projects in collaboration with industry partners to assay compounds for efficacy as enhancers of epithelial barrier function, or as modifiers of electrolyte transport, using in vitro cell lines and ex vivo tissue systems. We are using electrophysiological and biochemical approaches to determine functional responses and signaling pathways involved.