University or Institution

University of Pennsylvania

Area of Research:

Research Fellowship in Translational Gastroenterology and Inflammatory Bowel Disease Immunology

Primary Mentor:

Elizabeth Lennon, DVM, PhD, DACVIM (SAIM) and Dan Beiting, PhD, will serve as co-primary mentors. Dr. Lennon is a tenure-track Assistant Professor in the Department of Clinical Sciences and Advanced Medicine at the University of Pennsylvania School of Veterinary Medicine. Dr. Lennon has an NIH-funded research laboratory focusing on investigating the mucosal immunology of inflammatory bowel disease, with a focus on the role of the mast cell. As such, she has a fully equipped research laboratory, a full-time research technician, and equipment and infrastructure to support cell culture, animal, and molecular biology benchtop work. Dr. Lennon performs clinical work at the University of Pennsylvania School of Veterinary Medicine Internal Medicineservice.

Dr. Lennon is training a PhD candidate, a board-certified large animal internist, Dr. Jane Woodrow, who has passed her comprehensive examination and is anticipated to defend her PhD in December 2020. Dr. Lennon has also successfully mentored 3 veterinary students through summer research projects.

Mentorship contribution: Dr. Lennon will serve as a Clinician-Scientist career mentor, and will be responsible for study design, coordination of mentorship, relationship of the findings to OneHealth, instruction in mouse work and immunologic techniques, and overseeing successful progress towards completion of the fellowship, and coordinating the resources necessary for the fellow to be able to successfully write a K award application.

Dr. Beiting is a tenure-track Assistant Professor in the Department of Pathobiology at the University of Pennsylvania School of Veterinary Medicine. He is the co-director of the Center for Host-Microbial Interaction at PennVet, which is focused on developing collaborative projects related to OneHealth, genomics, and microbiology. Dr. Beiting teaches a semester-long course at PennVet (CAMB 714, DIYtranscriptomics.com), the only one of its kind at the university, that equips students with the skills for comprehensive analysis of RNAseq datasets. Dr. Beiting and his current postdoctoral fellow, via the VCIC, recently completed a large clinical trial investigating the effects of dietary therapy on the intestinal microbiome in canine chronic enteropathy/IBD. The manuscript is under review at Microbiome (impact factor 9.1). The changes in the canine microbiome in response to dietary therapy echoed those from publicly available datasets in children undergoing exclusive enteral nutrition. Dr. Beiting has used genomic techniques in OneHealth applications, and identified a novel drug target in Staphylococcus schleiferi, a canine pathogen that is opportunistic in humans. Dr. Beiting has mentored one previous postdoctoral fellow, Ana Misic, PhD, currently a Field Applications Scientist for Illumina, and is currently mentoring 3 additional postdoctoral fellows. Dr. Beiting has mentored 8 summer veterinary and undergraduate students, one who is now a PhD candidate, and two visiting PhD exchange students from Brazil.

Mentorship contribution: Dr. Beiting will mentor the fellow in study design, data analysis from high-throughput techniques, particularly RNA-seq, and bioinformatic analysis of genomic data generated in the study. Dr. Beiting will provide samples from his previous study of canine chronic enteropathy/inflammatory bowel disease.

Mentoring Team:

Additional co-mentors include Vesko Tomov, MD, PhD, Assistant Professor of Medicine and Meena Bewtra, MD, PhD, MPH, Assistant Professor of Medicine, who are both fellowship-trained gastroenterologists. Drs. Tomov and Bewtra are co-Principal Investigators of the IBD Immunology Initiative (I3). Dr. Tomov has current NIH funding and has 2 postdoctoral fellows in his laboratory. Dr. Bewtra has served as a primary research mentor to over 13 trainees including undergraduates, residents, and post-doctoral fellows who have been awarded a NIH K23, a NIH Loan Repayment Grant, an ACG Clinical Research Award and 2 Masters of Science in Clinical Epidemiology degrees. Mentorship contributions: Dr. Tomov will provide training on his published techniques for processing endoscopic biopsies, which will be replicated in dogs. Dr. Tomov will also provide access and training in CyTOF and his recently developed analysis pipeline. Dr. Bewtra will provide access to patient samples, clinical data, and mentorship in study design and incorporation of clinical data with the immunologic data. Both are K-awardees so will provide input on development of a K award application.

Description of Potential Research Projects:

The incidence of inflammatory bowel disease (IBD) has been increasing dramatically in the last 30 years. Because of the rapid rise of this debilitating disease, investigators have hypothesized that the increased incidence is due to environmental factors rather than genetic predisposition. Rodent models of IBD have largely been used to investigate the IBD pathophysiology and treatment. Although lab mice are an invaluable model for studying basic pathophysiological mechanisms of disease, they have limitations as a model system for diseases that have important environmental inputs, since they live in a rigorously controlled environment. In particular, studies in mice do not accurately model disease variability, predisposition, or response to treatment that are due to interactions with the human “exposome,” for example, exposure to early life antibiotics or C-section delivery, viral and bacterial infections, vaccines, and the pollutants and xenobiotics present in modern life. Therefore, results of some studies, particularly treatment trials, do not translate well to humans. In contrast, dogs share the lifestyle and environment of humans, and therefore could serve as naturally-occurring disease models that mimic the human

“exposome”. The incidence of inflammatory bowel disease in dogs, according to anecdotal experience in the absence of published statistics, has also been increasing dramatically in recent years, paralleling the experience in human medicine. Our laboratory is interested in comparative mechanisms in canine inflammatory bowel disease. This project will evaluate the epithelial and immune cell compartments of intestinal mucosal biopsies in human and canine patients with inflammatory bowel disease with the goal to identify novel genes or cell subtypes that are similarly altered in canine and human IBD. Therefore, our goal is to fill the gap between mouse and human research using dogs as naturally-occurring models of IBD. We will investigate the contributions of innate immune cells, including mast cells and macrophages, and to evaluate novel genes or cell subtype alterations that are similar between dogs and humans but are not evident in mice. The fellow will utilize cutting-edge research techniques, which could include the following, based on individual preference and study design: intestinal cell isolation, RNA sequencing and single cell RNAseq, flow cytometry and mass cytometry (CyTOF, including the technique and analysis pipeline), as well as the use of murine models of IBD to conduct rigorously controlled experiments. The infrastructure for collection of patient-derived samples leverages the IBD Immunology Initiative (I3) at PennMedicine and the Veterinary Clinical Investigations Center (VCIC) at PennVet. The University of Pennsylvania offers the unique advantage of a veterinary school closely associated (a single continuous campus) with a medical school in an Ivy-League setting that houses cutting-edge research resources to optimally enable high impact comparative and translational research. The I3 (http://www.i3study.org/) offers IRB-approved infrastructure for prospective collection of human clinical data, peripheral blood, and mucosal biopsy samples from IBD patients or control patients undergoing endoscopy. To date, over 1600 patients have been enrolled, and biopsies have been collected from over 600. Intestinal biopsy specimens are processed on the day of collection to prepare single-cell suspensions of live epithelial and immune cells. Once collected and isolated, these cells can be frozen and thawed for future analysis by flow cytometry, CyTOF (mass cytometry), or other assays. The PennVet VCIC provides the necessary support to recruit and enroll dogs in the study and to maintain rigorous records related to this study. Dog mucosal biopsies and blood samples will be collected and processed in an identical manner as I3 human samples in order to allow comparisons to be drawn between species. The postdoctoral fellow will have the opportunity to collect prospective patient-derived samples, but will also have access to biobanked human and dog samples.

Additional Training Opportunities:

The environment for postdoctoral fellows at Penn is ideal due to the rich postdoc community and resources through the Biomedical Postdoctoral Programs (BPP) and Biomedical Postdoctoral Council (BPC). The BPC coordinates career development, social, and institutional infrastructure to ensure a successful experience. Grant development workshops are held regularly, including frequent K award workshops. One-on-one grantsmanship consulting for K award applications is available at PennVet with Leslie King, PhD, who is a highly skilled grant editor utilized by even experienced faculty. Chalk Talks are held on an as-needed basis for faculty and postdocs who are planning to submit grants. Other opportunities include a Career Development Series (recent topics: 7/10/19: Negotiation Skills Workshop (6 hours), 5/23/19: Strengthening Your Leadership). Many Research-In-Progress Seminars occur each week including the Immunology Graduate Group Distinguished Seminar Series, the Institute for Immunology Research-In-Progress presentations, Division of Gastroenterology weekly Grand Rounds, Gastroenterology weekly Research-In Progress, and Microbiology seminar series. Responsible Conduct of Research training is available on a regular basis for postdoctoral fellows.

Contact Information for Interested Potential Trainees:

Elizabeth M. Lennon, DVM, PhD, DACVIM Assistant Professor of Medicine School of Veterinary Medicine University of Pennsylvania 3900 Delancey Street Philadelphia, PA 19104 (215)573-6552 [email protected]