Radiation, inflammation, infection, and toxins can damage the integrity of the gastrointestinal epithelium. Mechanisms that initiate, facilitate, and subsequently attenuate regeneration are essential to prevent long-term damage or disease. Post-transcriptional regulons are groups of functionally-related mRNAs regulated primarily by RNA-binding proteins, which enable rapid, tissue-specific responses to cellular damage. This type of regulation is especially important in highly proliferative tissues such as the intestinal epithelium, where RNA-binding proteins may serve as ?rheostats? for cellular and tissue adaptation. Our overarching goal is to identify novel strategies to enhance intestinal epithelial regeneration and improve therapies for patients, especially those who experience injury to the gastrointestinal epithelium as a result of radiation or chemotherapy. We discovered recently that epithelial regeneration is enhanced in mice with intestinal epithelial deletion of IMP1 (IGF2 mRNA-binding protein 1; also called IGF2BP1), in part via up-regulation of the autophagy pathway. Autophagy is a mechanism by which cells adapt and survive in response to stress. For example, recent studies in mouse models with autophagy gene deletion demonstrate increased susceptibility to irradiation-induced tissue damage. Defining the link between IMP1 and autophagy would contribute to an emerging paradigm of post-transcriptional regulons that serve as critical regulators of gastrointestinal epithelial regeneration.
Aim 1 will examine the molecular mechanisms by which IMP1 regulates autophagy gene translation. We will use cell biology assays as well as ribosome-profiling in epithelial cells from mice with Imp1 deletion to define direct roles for IMP1 in autophagy (and other) gene translation.
Aim 2 will evaluate how IMP1-mediated changes in autophagy contribute to stem cell dynamics at homeostasis using mouse models, autophagy assays, and enteroid-formation assays.
Aim 3 will evaluate intestinal stem cell-specific roles of IMP1 in autophagy-mediated repair during irradiation-induced injury and subsequent regeneration. We will use mouse models of Imp1 deletion together with chemical or genetic deletion of autophagy to define how IMP1 normally functions during irradiation-induced injury and regeneration and whether this is autophagy-dependent. Successful completion of this proposal has the potential for both scientific and clinical impact and will provide a basis for improved or novel therapies for patients with radiation-induced (and potentially other) injury to the intestinal epithelium.
This proposal aims to understand how the RNA-binding protein, IMP1, coordinates essential mechanisms of intestinal epithelial regeneration. Advances made with these studies will allow for the development of new therapeutic strategies that may augment autophagy (or other) pathways in order to restore intestinal epithelial homeostasis. This work has the potential to improve therapy for patients, especially patients who experience injury to the gastrointestinal epithelium as a result of radiation or chemotherapy.
