PROJECT SUMMARY/ABSTRACT
This K01 SERCA award will provide protected research time and mentoring to Diane Peters, DVM, MS, PhD
as she establishes an independent biomedical research career. Dual-trained as a veterinarian and
pharmacologist, Dr. Peters has a strong background in comparative medicine, animal models of human
disease, in vivo pharmacology, and protease biology. Through completion of the training and research aims
outlined in this proposal, she will expand her knowledge of inflammatory bowel disease (IBD) and build an
advanced technical skill set, to include immunofluorescent imaging, CRISPR/Cas9 genome editing and
gastrointestinal phenotyping methods, that will form a solid foundation for her planned independent research
program. IBD is a chronic condition that negatively impacts patient quality of life and is associated with a high
public health burden. There is no cure for IBD and a large percentage of affected individuals are unresponsive
to all available treatments. Glutamate carboxypeptidase II (GCPII) is zinc metallopeptidase that is highly
overexpressed in the two main subtypes of IBD: Crohn's disease and ulcerative colitis. The promise of GCPII
as a therapeutic target in IBD has been demonstrated in multiple independent preclinical studies, which have
shown that small molecule GCPII inhibitors have significant anti-colitis activity in three mechanistically-distinct
mouse models. While it is apparent that GCPII upregulation is relevant in both human and mouse IBD,
knowledge gaps exist regarding its function in disease. This K01 SERCA research will yield critical new data
relevant to the biology of GCPII in IBD. Specifically, in Aim #1 GCPII expression will be defined in normal and
IBD-affected gastrointestinal tissues of human and mouse IBD. In Aim #2, a novel knock-in mouse will be
generated that overexpresses human GCPII in the ileum and colon, followed by longitudinal characterization of
barrier function, gastrointestinal inflammation, microbiome composition and visceral pain response. It is
hypothesized that the localization of GCPII overexpression will be conserved in human and mouse IBD and
that adult mice with forced ileum and colon GCPII overexpression will spontaneously develop colitis.
Successful completion of these research aims will (1) increase our understanding of GCPII dysregulation in
IBD, (2) identify GCPII+ target cell populations with relevance to ongoing to drug development efforts and (3)
yield a novel mouse model of IBD that may have increased similarity to human disease. The proposed
research will be supervised by a multidisciplinary team of expert scientists and clinicians including: Dr.
Barbara Slusher, Director of Johns Hopkins Drug Discovery, Dr. Pankaj Jay Pasricha, Director of the Johns
Hopkins Center for Neurogastroenterology, Dr. Cynthia Sears, Director of the Johns Hopkins Germ Free
Murine Core, Dr. Robert Anders, Gastrointestinal Pathologist, Dr. Christine McDonald, expert in
Gastrointestinal Barrier Function, and Dr. Thaddeus Stappenbeck, Gastrointestinal Pathologist and expert in
Mucosal Immunity, who are well-suited to mentor Dr. Diane Peters in her translational IBD research career.