Thursday, November 21, 2024
11/21/2024
PROJECT SUMMARY Over 900,000 Americans are currently diagnosed with Ulcerative colitis (UC), an incurable inflammatory bowel disease of complex etiology. UC is multifactorial, with genetics, microbiota, and uncontrolled immune response leading to recurring colon ulcers and inflammation. With no defined cause, symptom management is critical for patients with this chronic condition. A major endpoint for clinical treatment of UC and other inflammatory bowel diseases is mucosal healing. Current UC therapeutics are predominated by anti- inflammatories. To expand this arsenal, it is important to establish exactly how ulceration prevention and wound healing occur such that these features can be enhanced in a targeted manner. Since our early published discovery that Adenomatous Polyposis Coli (APC) protein has both cytoplasmic and nuclear functions, our research has focused on mechanisms by which nuclear APC maintains normal intestinal homeostasis. To enable our analysis, we generated mice with mutations in APC which compromise nuclear import. These Apc-mNLS mice displayed decreased numbers of mucus-secreting goblet cells (GCs) and increased inflammation, chemokine expression, and tissue damage in response to treatment with the colon irritant DSS compared to their DSS-treated wild-type (WT) littermates. More recently, we published that in WT mice, DSS-treatment could induce a subset of distal colon GCs to express elevated APC levels. Similarly, colon tissue from human CD patients also displayed elevated APC protein level in most GCs, a phenotype not observed in unaffected tissue. Based on these striking results, we wondered whether the elevated APC in UC colon might be a response to ulceration in an attempt to restore normal colonic tissue homeostasis. As such, we sought to determine the mechanistic basis for and cellular consequences of higher APC protein levels in UC tissue. RNA-seq analysis of normal colon cells depleted for APC revealed a set of genes significantly downregulated. Cross-referencing this list with APC ChIP-seq data as well as genes whose expression is altered in UC, we identified 7 genes with roles in wound repair and mucus barrier production that are candidates for transcriptional regulation by nuclear APC. We hypothesize that nuclear APC promotes wound repair and resolution of UC through driving transcription of the major mucus barrier component MUC2 as well as specific wound repair mediators. This hypothesis will be tested by addressing the following questions: Does nuclear APC 1) regulate transcription of modulators of inflammation and wound repair (AIM1)? 2) promote colon wound healing (AIM2)? 3) promote mucus layer generation and thereby impede microbial penetration, alter microbial composition and prevent inflammation (AIM3)? Answering these questions is expected to establish nuclear APC as a key contributor to wound repair, a finding that could ultimately be translated into new therapies for UC and other IBDs.
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