Evaluation of endoplasmic reticulum stress in the ileal reservoir mucosa of patients with ulcerative colitis and familial adenomatous polyposis

• Grant number: 24/12833-1
• Support Opportunities: Regular Research Grants
• Start date: February 01, 2025
• End date: January 31, 2027
• Field of knowledge: Biological Sciences - Immunology - Immunogenetics
• Principal Investigator: Raquel Franco Leal
• Grantee: Raquel Franco Leal
• Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated researchers: Licio Augusto Velloso ; Marciane Milanski Ferreira ; Maria de Lourdes Setsuko Ayrizono

Abstract

Total colectomy with anastomosis of the ileal pouch (IP) to the anal canal is the surgery of choice for patients with ulcerative colitis (UC) refractory to clinical treatment; and for familial adenomatous polyposis (FAP) with multiple polyps in the rectum. Primary pouchitis is one of the most common postoperative complications in UC patients and is rare in FAP. Previous studies from our research group have shown an increase in pro-inflammatory cytokines, as well as changes in apoptosis and macroautophagy pathways in the IP mucosa of UC patients when compared to FAP and normal distal ileum controls. However, no studies evaluated the endoplasmic reticulum stress (ERE) pathways, which are associated with apoptosis and autophagy mechanisms. In this sense, studies need to evaluate the ERE pathways in the IP mucosa and afferent loop of UC and PAF patients undergoing total rectocolectomy compared with controls of normal distal ileum. Thirty patients with ileoanal pouch anastomosis with "J" IP will be studied regarding the gene expression of IRE1 (ERN1), PERK (EIF2AK3), ATF6, GRP78 (HSPA5), GRP94 (HSP90B1), ATF3, STC2, DDIT3 DNAJC3, and CALR. The proteins p-eIF2±, sXBP1, ATF6, GRP78, and GRP94 will also be evaluated by immunohistochemistry. The control group will consist of 15 patients with normal ileocolonoscopy. Biopsies will be obtained and analyzed by extraction and quantification of mRNA and cDNA by polymerase chain reaction (PCR) in real-time. The absence of pouchitis will be determined by clinical, histological, and endoscopic parameters, according to the Pouchitis Disease Activity Index (PDAI). The study was approved by the Local Research Ethics Committee. Nonparametric tests will be applied for statistical analysis, with significance at p<0.05. The transcriptional and protein changes are expected to contribute to a better understanding of the factors that predispose to the inflammatory process in IP, to bring scientific advances and contributions to the discovery of the pathophysiological mechanisms that justify the difference in the incidence of pouchitis between the two diseases, as well as to identify possible new therapeutic targets and biomarkers of this inflammatory process. (AU)