The intestinal epithelium exhibits a remarkable ability to self-renew owing to the continuous proliferation and differentiation of two postulated intestina stem cell (ISC) populations. Crypt base columnar cells (CBCs) are thought to actively cycle and express the surface cell marker LGR5, whereas the +4 cells are a quiescent population that expresses transcription factors such as BMI1 and HOPX. Much of the current knowledge about ISC regulation and response comes from studies of radiation-injury models in mice where ISCs themselves are damaged. It remains unknown how ISCs respond to damage at other sites within the intestinal epithelium such as might occur following exposure to rotavirus (RV) infection, which damages epithelial cells at the villus tip. Understanding the role of proliferatin ISCs in response to RV infection is significant for advancing scientific knowledge on stem cell regulation as well as promoting future application of this knowledge to treat epithelial injury through regeneration. The long-term goal of the proposed research is to identify how ISC populations respond to RV-mediated damage to the human intestinal epithelium. I hypothesize that RV-infected cells mediate a crosstalk to the proliferative compartment, inducing the plasticity of ISCs and the activation of a subpopulation of +4 cells, which ultimately leads to the restoration of the intestinal epithelium. This hypothesis is based on preliminary data demonstrating that RV infection can affect ISC function in vivo and in vitro. Using the novel, human intestinal enteroids (HIEs) as a model, I propose [1] to identify the signaling pathways that link RV infection to ISC proliferation, and [2] to examine the ISC plasticity that is induced y RV infection. The results from the proposed project are expected to significantly advance our current understanding of ISC response to damage and deliver new insights on the pathways regulating intestinal epithelial homeostasis.

Public Health Relevance

The activities of intestinal stem cells are crucially important for maintaining the homeostasis of the human intestinal epithelium and understanding the biological processes regulating the intestinal stem cells is critical for dissecting disease pathogenesis and pioneering regenerative medicine. I propose to study the response of intestinal stem cells to rotavirus infection, which frequently causes intestinal damage and regeneration. My hope is to utilize results from this project to identify potential therapeutics for the treatment of intestina injury.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZDK1)
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Densmore, Christine L
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Baylor College of Medicine
Schools of Medicine
United States
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Zou, Winnie Y; Blutt, Sarah E; Zeng, Xi-Lei et al. (2018) Epithelial WNT Ligands Are Essential Drivers of Intestinal Stem Cell Activation. Cell Rep 22:1003-1015
Zou, Winnie Y; Blutt, Sarah E; Crawford, Sue E et al. (2017) Human Intestinal Enteroids: New Models to Study Gastrointestinal Virus Infections. Methods Mol Biol :