The proposed training in this K01 application outlines an integrated plan of mentored research and career development activities as well as a specific strategy for my pathway to an independent research career in intestinal epithelial biology. This award will allow me to refine existing and gain additional skills with the guidance of my research mentor, Dr. Rustgi, as well as an interdisciplinary advisory committee of Drs. Wu (Chair), Kaestner, Lengner, and Lynch. In addition to the advice from my mentor and committee, I will pursue formal coursework in stem cell and RNA biology, and biostatistics/bioinformatics, as well as seminars in career development skills including bioethics, grant/manuscript writing and laboratory management. During this award period I will present my work, both formally and informally, at national research conferences (DDW, Experimental Biology, Keystone, Gordon Conferences), at floor lab meetings through the NIDDK P30 Center for Molecular Studies in Digestive and Liver Diseases and Division of Gastroenterology, and at meetings of the UPenn constituency of the NIDDK/NIAID U01 Intestinal Stem Cell Consortium. Through this proposal, I will explore the role of IMP1 mRNA binding protein as a modulator of intestinal homeostasis through the use of existing and novel mouse models, innovative ex vivo 3D cultures techniques, and RNA-immunoprecipitation-sequencing. We hypothesize that IMP1 is a critical modulator of normal intestinal homeostasis and response to injury, through cell-type specific effects in the epithelial and mesenchymal compartments of the intestine.
In Aim 1, we will utilize mouse models to conditionally knockout Imp1 in specific tissue compartments (epithelial or mesenchymal), in order to elucidate the relative contribution of Imp1 in specific cll types during normal homeostasis and injury.
In Aim 2, we have developed and will test a novel Imp1 reporter mouse, which will be used as a lineage-tracing model for Imp1+ cells and will also allow for specific and temporal ablation of Imp1+ cells. We will utilize the mouse models from Aim 1 for complimentary ex vivo enteroid cultures of intestinal crypts and niche components, and mechanistic studies identifying novel mRNA binding targets of Imp1. We anticipate that results from these studies will define Imp1's role in intestinal homeostasis (through direct actions on epithelial crypts or through modulation of peri-cryptal niche components), the direct consequence of Imp1 loss in the neonatal period and adulthood during normal intestinal homeostasis and challenge with injurious agents, and novel Imp1 mRNA binding targets that will provide the foundation for future studies with translational application in diagnosis and therapy of intestinal diseases. Studies of IMP1 will elucidate novel mechanisms of post-transcriptional regulation of intestinal epithelial growth, with potential to contribute significantly to our understanding of intestinal health and disease.
Studying the role that specific factors play in normal intestinal biology is critical for the understanding of disease processes and the development of new therapeutics. We are examining a factor called IMP1 that is critically important during development of the intestine, but may also promote transformation to cancer when inappropriately activated. Results from our studies will lead to a more precise understanding of IMP1 in normal intestinal biology and provide the basis for future studies with translational applications in diagnosis and therapy for various intestinal diseases.
|Hamilton, Kathryn E (2018) Microfabricated Crypt Scaffolds: A New Foundation for Evaluating Human Colon Stem Cells. Cell Mol Gastroenterol Hepatol 5:161-162|
|Kasagi, Yuta; Chandramouleeswaran, Prasanna M; Whelan, Kelly A et al. (2018) The Esophageal Organoid System Reveals Functional Interplay Between Notch and Cytokines in Reactive Epithelial Changes. Cell Mol Gastroenterol Hepatol 5:333-352|
|Chatterji, Priya; Hamilton, Kathryn E; Liang, Shun et al. (2018) The LIN28B-IMP1 post-transcriptional regulon has opposing effects on oncogenic signaling in the intestine. Genes Dev 32:1020-1034|
|Hall, Timothy M; Tétreault, Marie-Pier; Hamilton, Kathryn E et al. (2018) Autophagy as a cytoprotective mechanism in esophageal squamous cell carcinoma. Curr Opin Pharmacol 41:12-19|
|Mizuno, Rei; Chatterji, Priya; Andres, Sarah et al. (2018) Differential Regulation of LET-7 by LIN28B Isoform-Specific Functions. Mol Cancer Res 16:403-416|
|Giroux, Véronique; Stephan, Julien; Chatterji, Priya et al. (2018) Mouse Intestinal Krt15+ Crypt Cells Are Radio-Resistant and Tumor Initiating. Stem Cell Reports 10:1947-1958|
|Giroux, Véronique; Lento, Ashley A; Islam, Mirazul et al. (2017) Long-lived keratin 15+ esophageal progenitor cells contribute to homeostasis and regeneration. J Clin Invest 127:2378-2391|
|Whelan, Kelly A; Merves, Jamie F; Giroux, Veronique et al. (2017) Autophagy mediates epithelial cytoprotection in eosinophilic oesophagitis. Gut 66:1197-1207|
|Long, Apple G; Lundsmith, Emma T; Hamilton, Kathryn E (2017) Inflammation and Colorectal Cancer. Curr Colorectal Cancer Rep 13:341-351|
|Almohazey, Dana; Lo, Yuan-Hung; Vossler, Claire V et al. (2017) The ErbB3 receptor tyrosine kinase negatively regulates Paneth cells by PI3K-dependent suppression of Atoh1. Cell Death Differ 24:855-865|
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