The role of the RNA binding protein IMP1 in intercellular communication and necrotizing enterocolitis

PROJECT SUMMARY
Necrotizing enterocolitis (NEC) is a devastating inflammatory disease that affects the intestine of premature
infants. There is major gap in our understanding of the pathophysiology of NEC, including no cure for this often
deadly disease. This proposal aims to help fill the knowledge gap by defining the role of the developmentally
expressed mRNA binding protein IMP1 in the intestine during NEC. IMP1 plays roles in intestinal barrier
maintenance, immune cell activation, intestinal stem cells, autophagy, and extracellular vesicles (EVs), which
could all effect NEC etiology; however, the role of IMP1 in NEC is not known. Herein I will test the hypothesis
that the RNA binding protein IMP1 post-transcriptionally promotes direct cell-to-cell and indirect vesicle-mediated
communication in the intestine to impact barrier and immune function and NEC development. In Aim 1, we will
utilize genetic mouse models where Imp1 is conditionally deleted or overexpressed in the intestinal epithelium
to compare physiological and molecular responses to NEC challenge with a focus on intestinal barrier function.
We will perform RNA immunoprecipitation (RIP)-sequencing to identify novel Imp1 binding targets in the neonatal
intestine and during NEC, validate key targets in patient-derived enteroid models, and examine mechanisms in
monolayer culture systems. In Aim 2, we will identify the role of Imp1 in EV communication and intestinal
macrophage activation to protect against NEC. This will be achieved through direct analysis of EV cargo and
intestinal macrophages. We will examine interactions between EVs, immune cells, and the epithelium using
murine and patient-derived enteroids to define mechanisms governing barrier function and NEC etiology. Studies
of IMP1 will elucidate novel mechanisms of post-transcriptional regulation of intestinal epithelial communication,
with the potential to contribute significantly to our understanding of NEC.
My goal is to become a successful, independent scientist and a leader in the field of gastroenterology, with the
long-term goals of identifying new therapeutic targets to improve NEC treatment and ultimately NEC prevention.
During this mentored career development award, I will refine existing and gain additional skills with the guidance
of my research mentoring committee, Drs. Wong, Good, Marks, Scottoline, Saugstad, and Brody. In addition to
the advice from my mentors and collaborators, I will pursue coursework in immunology and post-transcriptional
regulation, as well as seminars in career development skills including bioethics, grant/manuscript writing,
leadership, and laboratory management.

Grant Number: 5K01DK129401-04
NIH Institute/Center: NIH
Principal Investigator: Sarah Andres