Project Summary
This proposal details a 5-year training plan to aid the continued develop of Dr. Sarah Short, Ph.D. into an
independent GI researcher. This research plan will focus on elucidating the role of glutathione peroxidase 1
(GPx1), a ubiquitously expressed selenoenzyme and potent antioxidant, in inflammatory bowel disease (IBD)
and colitis-associated dysplasia (CAD). Compelling preliminary data using Gpx1-/- mice indicates that unlike
many antioxidants whose loss exacerbates murine colitis, loss of GPx1 confers striking protection from dextran-
sodium sulfate (DSS)-induced colitis. GPx1 deficiency also increases survival and stemness in 3D organoids
and alters metabolism in tissue culture cells, which may additionally promote regeneration and wound healing.
GPx1 expression also modifies immune cell function, as Gpx1-/- bone marrow-derived macrophages have
heightened response to “M2” stimuli and decreased migratory ability. Together, these results suggest that GPx1
augments inflammatory injury through alterations in both epithelial and immune cell function.
Based on these finding, the hypothesis of this proposal is that GPx1 is detrimental in inflammatory bowel
disease by altering stem cell function, redox homeostasis, and immune responses. Further, inhibiting GPx1
activity may be an effective therapeutic strategy. This hypothesis will be tested in two specific aims to determine
how GPx1 contributes to intestinal epithelial cell homeostasis, oxidative stress, colitis, and colitis-associated
dysplasia. The first aim will investigate epithelial function, capitalizing on Dr. Short’s over 10 years of experience
in epithelial cell biology and barrier function. The second aim will complement epithelial-based studies by
determining how GPx1 loss alters immune cell recruitment, differentiation, and function, and identify how these
changes modify intestinal injury responses. In addition to being the logical “next step” experiments in defining
GPx1 function, these experiments provide the perfect framework to further Dr. Short’s development in aspects
of mucosal immunology which contribute to intestinal diseases, and will include new training in flow cytometry,
chemokine analysis, bone marrow transplantation, and the T-cell transfer colitis model. Dr. Short’s career
development will be further enhanced by regular discussions with primary mentor, Dr. Christopher Williams, and
her mentoring committee consisting of Drs. Keith Wilson, Jeremy Goettel, and Sean Davies. All studies and
training will take place at Vanderbilt, and the institution, Department of Medicine, and Gastroenterology Division
are highly supportive of Dr. Short’s academic career and fully support her application.
Dr. Short’s ultimate goal is to become an independent academic researcher focusing on mechanisms which
regulate development and severity of IBD and colitis-associated cancer that can lead to improved therapeutic
options for these patients. Interestingly, both specific aims proposed in this application will evaluate GPx1 as a
therapeutic target using tiopronin, which is FDA-approved and well-tolerated. Together, these training
experiences will ensure Dr. Short is poised to direct a well-rounded independent research program in IBD.