One of the challenges for the management of ulcerative colitis (UC; a subtype of inflammatory bowel disease) is the lacking of a predictive biomarker that can help stratify patients for personalized treatment strategies. We have previously shown that in Crohn?s disease (CD; another subtype of inflammatory bowel disease), the morphologic phenotype of small intestinal Paneth cells readily predicts outcome in post-surgical CD patients. Given the shared genetic etiology and clinical features between CD and UC, we hypothesize that Paneth cell phenotype will also predict outcome in UC. Our long-term goal is to define the clinical indications of inflammatory bowel disease of which Paneth cell phenotype can predict outcome. The objective of this grant is to determine to the extent of which Paneth cell phenotype predicts development of ileal complications in UC. The central hypothesis is that in UC patients undergoing total colectomy and ileal pouch anal anastomosis (IPAA), the Paneth cell phenotype obtained at time of colectomy will predict development of pouchitis and de novo CD in the ileal pouch. Our rationale is that Paneth cell phenotype will offer better outcome prediction over current practice.
Our specific aims will test the following hypotheses:
(Aim1) Paneth cell phenotype correlates with ileal complications in UC patients with IPAA;
(Aim 2) Deep learning will reduce observer variation and enhance rigor and reproducibility of Paneth cell phenotype analysis in surgical pathology specimens, and also identify novel clinical factors that correlate with Paneth cell function;
(Aim 3) Serum markers that correlate with Paneth cell phenotype could be used to predict outcome in UC. Upon conclusion, we will understand the role for Paneth cell function in modulating disease course in IBD. This contribution is significant since it will establish Paneth cell phenotype as a critical predictive biomarker for IBD. The proposed research is innovative because we use state-of-the-art deep learning approach to build an imaging analysis pipeline, and to identify novel clinical factors that affect Paneth cell functions. Identifying how epithelial cells with innate immune function affect disease course will provide insight into other inflammatory disorders.
The proposed research is relevant to the public health because ulcerative colitis, which is increasing in prevalence worldwide, represents a major national cost measured by both patient suffering and economic burden. Despite significant advances in care, clinical trial data demonstrate remission rates is at best of 40%. Strategies that stratify patients based on Paneth cell function represent a novel approach for outcome prediction. Upon conclusion, we will establish that Paneth cell phenotype is a predictive cellular biomarker for ileal complications in ulcerative colitis patients undergoing total colectomy and ileal pouch anal anastomosis. We will also define the underlying genetic associations and molecular pathways of abnormal Paneth cell phenotype in these patients. In addition, we will develop deep learning algorithms that will streamline the interpretation of Paneth cell phenotype for pathology specimens, and define serum markers that correlate with Paneth cell phenotype to allow for less invasive and more frequent monitoring.
