Specific Aim 1: Define genetic determinants of unmet medical needs in IBD. Sub-aim 1a: Define genetic factors associated with true non-response (TNR), pharmacokinetic, and immunogenic parameters of biologic therapies in IBD. Sub-aim 1b: Define genetic variation associated with perianal Crohn’s disease.
Specific Aim 2: Functional characterization of genetic risk variants associated with IBD. Sub-aim 2a: Characterization of the regulatory landscape in ileal CD tissues. Sub-aim 2b: Functional characterization of tissue specific regulatory and transcriptomic landscapes for IBD risk loci. Expression quantitative trait locus (eQTL) analysis of IBD risk regions. Connecting IBD-associated regulatory variants to target genes using chromosome conformation capture assays.
Specific Aim 3: Defining novel genetic determinants and environment interplay of Paneth cell phenotypes in CD patients. Determine the genetic associations, molecular mechanisms, and clinical relevance of Paneth cell defects in European ancestry, East Asian, African American, and Hispanic IBD patients.
Aim 1: To quantify histomorphometric (HM) features within tissue architecture that are associated with disease recurrence following surgery for CD. Each category requires separate training data to develop a single classification algorithm that identifies all categories of interest at once in whole slide H&E images.
Aim 2: To determine the molecular underpinnings and genetic associations of HM features in CD and build prediction models for disease recurrence with integration of HM, genomic, clinical and transcriptomic features.
Jon Braun (Cedars): Biomarking IBD patient-specific disease features using the epithelial antigenic peptidome
Dr. Stappenbeck is a practicing pathologist and an internationally recognized leader in the study of epithelial stem cells in inflammatory bowel disease and colorectal cancer. Dr. Stappenbeck was recruited to Cleveland Clinic from Washington University School of Medicine in St. Louis, where he was the Conan Professor of Pathology and Immunology and co-chief of the Division of Laboratory and Genomic Medicine. He earned a combined MD/PhD degree at Northwestern University and completed a residency and fellowship in pathology at Washington University. He is an elected member of several honorary societies, including the Association of American Physicians and American Society for Clinical Investigation.
Dr. Liu is an Assistant Professor of Pathology and Immunology, Division of Anatomic and Molecular Pathology, Washington University School of Medicine. Dr. Liu’s main research interest is in the role of Paneth cells in Crohn’s Disease. In particular, he is interested in the molecular mechanisms of how morphologic patterns of cytoplasmic antimicrobial granules are affected by genetics and environmental triggers, and their clinical relevance. Dr. Liu’s research interests also include developing disease pathogenesis-relevant prognostic biomarkers.
Dr. Gayther’s research program is focused largely on understanding the underlying causes of ovarian cancer initiation and development. Dr. Gayther has a long, established track record in defining the heritable component of ovarian cancer, and the functional role of both common and rare risk variants and their target susceptibility genes in the early-stage disease pathogenesis. The overall approach of this research program is to integrate genomics and epigenomics analyses to identify molecular markers associated with disease, with cell biology modeling studies to validate the role of novel molecular markers in disease biology. The goal is to translate the findings from these studies into the clinical arena to improve risk prediction and prevention strategies, early-stage screening and disease diagnosis and targeted therapeutics for patients.
Dr. Hazelett has a broad background in both experimental and computational biology. He relies on a systems-biology approach involving the analysis and synthesis of next-generation sequencing data. His most recent contributions are highlighted by efforts to annotate and draw inference from the functional consequences of genetic associations from genome-wide association studies (GWAS) for prostate cancer, Hodgkin’s lymphoma and ovarian cancers. Toward this goal, Dr. Hazelett integrated GWAS and next-generation sequencing data from my collaborators with public datasets such as1000 genomes and the Encyclopedia of DNA elements (ENCODE) to infer new diseases variants outside of transcribed sequences. He has recently begun independent efforts as a principal investigator at Cedars-Sinai Medical Center, using novel approaches to achieve a greater understanding of the relationship between the regulatory code and genetic disease variants.
Dr. Gertych’ research interests are focused on computational pathology which he uses as a platform to quantitate morphologic patterns of tumors at the tissue and single cell level to understand functional relationships between cells in the tumor microenvironment. The computational pathology provides opportunities to develop a new class of biomarkers that can be integrated with other -omics data to improve the prediction of disease outcomes and response to treatment in the era of precision medicine. Dr Gertych’s recent scientific contributions are focused on urologic and pulmonary malignancies.
A native of Cleveland, Ohio, Dr. Braun was raised in Los Angeles, where he studied violin, and continues his interests in musical performance and poetry. After studies at Stanford University, Harvard Medical School, Brigham and Women’s Hospital, and Whitehead Institute, he joined the faculty at the UCLA School of Medicine, where he served as chair of pathology and laboratory medicine. In 2019, he joined the Inflammatory Bowel and Immunobiology Research Institute of Cedars-Sinai Medical Center, to study human cohort-based biology of mucosal-microbiome interaction in IBD via multi’omic methods. His recent activities included participant or PI roles in NIH HMP2, the CCF Microbiome Consortium, the CORALE SeroNet NCI consortium, and the NIDDK IBD Genetics Consortium. This work has identified allelic variation of IBD-associated loci, notably mucin o-glycan structures, on microbiome composition and function, and mechanisms of pre-disease and disease activity states. His ancillary project with the NIDDK IBD Genetics Consortium searches for genome-wide targets of anti-epithelial autoimmunity, and their potential role in IBD disease phenotypes.