Endoplasmic reticulum (ER) stress is an ancient conserved mechanism that allows cells, especially those with significant secretory function such as intestinal epithelial cells (IEC), to cope with the emergence of misfolded or unfolded proteins within the ER through a mechanism called the Unfolded Protein Response (UPR). The UPR consists of three ER-associated pathways that signal adaptive transcriptional programs within the nucleus. The most highly conserved pathway is that related to inositol requiring enzyme 1 (IRE1) which, through its endoribonuclease and kinase activities, regulates the transcriptional activity of X-box binding protein 1 (XBP1) and Jun related kinase (JNK), respectively. Deletion of the XBP1 gene specifically within IECs leads, uniquely, to spontaneous enteritis and sensitivity to colitis-inducing agents in association with increased ER stress, loss of Paneth and goblet cell function, an inability to manage luminal microbial challenges and a hypersensitivity of the IEC to signals emanating from bacterial and immune factors. XBP1 function with the IEC thus affects the two central determinants of IBD pathogenesis;the microbiota and immune response to the microbiota itself. Given that ER stress is readily demonstrable in animal models of inflammatory bowel disease (IBD) and the human condition and that the XBP1 gene harbors polymorphisms that confer risk for the development of IBD, it is reasonable to propose that the host's ability to manage ER stress within the IEC that is caused by environmental factors including inflammation itself is an important issue in understanding IBD pathogenesis. The current proposal aims to: (1) Elucidate the molecular pathways that connect unabated ER stress with inflammation that occurs in the presence of hypomorphic XBP1 function within the epithelium by characterizing the activity of the three major UPR pathways, the role NFkB activation, the potential intersection between ER stress and autophagy pathways, the effects of XBP1 deficiency on specific epithelial subtypes of epithelial cells and a determination of whether blockade of NFkB or JNK can ameliorate XBP1-related inflammation;(2) Define the inflammatory mediators derived from the epithelium that are involved in inflammation and their effects on mucosal immune cell populations by defining the role of TNFa and the characterization of the gut associated lymphoid cell populations in the intestines of XBP1-deficient mice, and;(3) Define the environmental factors involved in the exacerbation or alleviation of inflammation associated with XBP1- deficiency by characterizing the microbiome of XBP1-deficient mice and the role of the microbiota in inducing spontaneous enteritis and susceptibility to colitis and establishing whether agents that reduce ER stress can abrogate the intestinal inflammation arising from XBP1-deficient epithelia. These animal models and their interrogation provide a unique opportunity to identify and test novel therapeutic approaches for the treatment and prevention of IBD that may be generally extensible to IBD patients with a wide-range of phenotypic and genetic pedigrees.

Public Health Relevance

XBP1 function within intestinal epithelial cells (IEC) is associated with endoplasmic reticulum (ER) stress and affects the two central determinants of inflammatory bowel disease (IBD) pathogenesis;the bacteria found in the gastro-intestinal tract and immune response to these bacteria itself. Given that ER stress is readily demonstrable in animal models of IBD and the human condition, and that the XBP1 gene harbors polymorphisms that confer risk for the development of IBD, we propose that the host's ability to manage ER stress within the IEC that is caused by environmental factors including inflammation itself is an important issue in understanding IBD pathogenesis. These animal models and their interrogation provide a unique opportunity to identify and test novel therapeutic approaches for the treatment and prevention of IBD that may be generally extensible to IBD patients with a wide-range of phenotypic and genetic pedigrees.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK088199-04
Application #
8465875
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Grey, Michael J
Project Start
2010-05-01
Project End
2015-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
4
Fiscal Year
2013
Total Cost
$511,357
Indirect Cost
$163,169
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Blumberg, Richard S (2016) Environment and Genes: What Is the Interaction? Dig Dis 34:20-6
Lin, Jieru E; Colon-Gonzalez, Francheska; Blomain, Erik et al. (2016) Obesity-Induced Colorectal Cancer Is Driven by Caloric Silencing of the Guanylin-GUCY2C Paracrine Signaling Axis. Cancer Res 76:339-46
Grootjans, Joep; Kaser, Arthur; Kaufman, Randal J et al. (2016) The unfolded protein response in immunity and inflammation. Nat Rev Immunol 16:469-84
Krishnamoorthy, Sriram; Liu, Tongyao; Drager, Douglas et al. (2016) Recombinant factor VIII Fc (rFVIIIFc) fusion protein reduces immunogenicity and induces tolerance in hemophilia A mice. Cell Immunol 301:30-9
Arabzadeh, Azadeh; Dupaul-Chicoine, Jeremy; Breton, Valérie et al. (2016) Carcinoembryonic Antigen Cell Adhesion Molecule 1 long isoform modulates malignancy of poorly differentiated colon cancer cells. Gut 65:821-9
Nakanishi, Yuki; Reina-Campos, Miguel; Nakanishi, Naoko et al. (2016) Control of Paneth Cell Fate, Intestinal Inflammation, and Tumorigenesis by PKCλ/ι. Cell Rep 16:3297-310
Hosomi, Shuhei; Kaser, Arthur; Blumberg, Richard S (2015) Role of endoplasmic reticulum stress and autophagy as interlinking pathways in the pathogenesis of inflammatory bowel disease. Curr Opin Gastroenterol 31:81-8
Zeissig, Sebastian; Petersen, Britt-Sabina; Tomczak, Michal et al. (2015) Early-onset Crohn's disease and autoimmunity associated with a variant in CTLA-4. Gut 64:1889-97
Pyzik, Michal; Rath, Timo; Lencer, Wayne I et al. (2015) FcRn: The Architect Behind the Immune and Nonimmune Functions of IgG and Albumin. J Immunol 194:4595-603
Rath, Timo; Baker, Kristi; Dumont, Jennifer A et al. (2015) Fc-fusion proteins and FcRn: structural insights for longer-lasting and more effective therapeutics. Crit Rev Biotechnol 35:235-54

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