The highly secretory intestinal epithelial cell (IEC), in general, and Paneth cell (Pc), in particular, are exquisitely sensitive to endoplasmic reticulum (ER) stress due to unfolded and misfolded proteins and depend upon the unfolded protein response (UPR) and highly integrated pathway of UPR-regulated autophagy, to maintain homeostasis and avoid spontaneous enteritis and epithelial derived neoplasia due to disturbances in the intestinal stem cell (ISC) niche. The current research proposal addresses the unanswered question of how disturbances of the UPR and autophagy through an examination of X box binding protein 1 (XBP1) and autophagy related 16-like 1 protein (ATG16L1), respectively, result in epithelial abnormalities and spontaneous enteritis. Our long-term goals are therefore to parse out the specific consequences of and molecular pathways involved in IEC-derived, ER stress and autophagy associated enteritis. The objectives of the proposed studies are therefore to better elucidate how such enteritis emerges and the specific roles played by the innate and adaptive arms of the immune system in mediating IEC initiated intestinal inflammation, understand how ER stress and diminished autophagy in the Pc results in a specific crypt-associated expansion of enteroendocine (EE) cells and illuminate an unforeseen potential role of intelectin-1 in IEC centered, ER stress-induced intestinal inflammation. Our central hypothesis is that unresolved ER stress in the IEC, and especially the Pc, that is de- rived from a genetically-imposed inability of the UPR and autophagy to cope with physiologic (e.g. the com- mensal microbiota) and/or pathophysiologic (environmental) demands results in numerous primary epithelial disturbances. The rationale for these studies is that ER stress in IECs affects the Pc-ISC niche and are sensed by the immune system. Our central hypothesis will be tested by the following three specific aims: 1) define the role of the immune system in responding to ER stressed epithelium; 2) elucidate ER stress and autophagy interactions in the Pc-ISC niche, and; 3) determine the function of intelectin-1 in mediating the consequences of XBP1-deficiency in the Pc.
In Aim 1, we will seek to understand the mechanisms by which group 1 innate like lymphoid cells sense natural-killer group 2 member D ligands on ER stressed IEC and induce enteritis and identify the microbial and epithelial factors that trigger dendritic cells to induce protective IgA+ plasma cells and mechanisms involved.
In Aim 2, we will determine whether ATG16L1 compensates for and prevents spontaneous enteritis in XBP1-deficient Pc and how Pc associated ER stress disturbs the ISC niche and the role played by autophagy.
Aim 3 will ascertain whether a metabolic disturbance represents a fundamental property of the XBP1-deficient epithelium and the role of intelectin-1 in these metabolic and inflammatory disturbances. Over- all this proposal is significant because it will further define the mechanisms by which the UPR and autophagy regulate IEC and Pc homeostasis which we predict will lead to highly precise means to define specific sub- types of IBD and facilitate new therapeutic approaches that are fine-tuned to a molecularly defined pathway.
The proposed research is relevant to public health because endoplasmic reticulum stress and autophagy represent highly integrated and genetically determined pathways that are critically involved in environmental sensing and thus central to understanding the pathogenesis of inflammatory bowel disease (IBD). The proposed studies are relevant to the mission of the NIDDK because they are expected to identify highly precise means to define specific subtypes of IBD and facilitate new therapeutic approaches that are fine-tuned to a molecularly defined pathway.
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