The following projects will focus on a variety of single-cell analysis techniques to build a Gut Cell Atlas. Researchers will procure human tissue from both healthy individuals and those with Crohn’s disease, and gather data for gene and protein expression and cellular localization.
The goal of this study is to build a detailed reference atlas of the cell types, and the genes they express, of the healthy terminal ileum and ascending colon, and a corresponding reference atlas of Crohn’s disease and use them to decipher the molecular basis of intestinal function and inflammatory disease processes in CD. This grant will also identify characteristic molecular, cellular, and histological changes in disease that can be targeted therapeutically or serve as potential biomarkers.
Team: Aviv Regev, Ramnik Xavier, Kristin Ardlie, Evan Macosko, Fei Chen, Xiaowei Zhuang, Barbara Engelhardt, Sarah Teichman, Carl Anderson and Mathias Zilbaur
The goal of this study is to provide an integrated dataset of single-cell gene expression data mapped onto a high-resolution 3-dimensional framework from intestines (terminal ileum and ascending colon) of healthy individuals and Crohn’s disease patients undergoing resection due to intestinal obstruction or stricturing disease. This grant will also provide a gut-centric coordinate framework to map anatomical locations of cells providing novel insights into Crohn’s disease mechanisms, crucial to developing personalized therapeutic strategies, and new analytical tools for querying the Gut Cell Atlas database.
Team: Shahida Din, Richard Baldock, Albert Burger, Irene Papatheodorou, David Adams
The goal of this study is to identify and characterize cell types and disease-specific gene expression patterns and regulatory features by establishing a comprehensive cellular atlas of the ileum and colon in healthy individuals and patients with ileal-colonic and ileal Crohn’s disease. This grant will also establish intestinal epithelial organoids and provide cell specific gene expression and epigenetic data to understand how similar or different these models are from the cells in the body and help explain the mechanisms of Crohn’s disease.
Team: Eugene Chang, Sebastian Pott, Matthew Stephens
The goal of this study is to construct an atlas of the terminal ileum and ascending colon containing single-cell gene expression and spatial information from biopsy and surgical samples from both healthy individuals and Crohn’s disease patients with varying degrees of inflammation. This grant will also provide tools to integrate the data from the multi-modality analysis of terminal ileal and colonic tissues, and related clinical data, including demographics and medications to correlate inflammation on the cellular level with patient history, symptoms and response to medications.
Team: Lori Coburn, Qi Liu, Ken Lau, Bennett Landman, Gregor Neuert
The following projects will focus on particular cell types within the gut – gut-associated lymphoid tissues, enterochromaffin cells, macrophages and stem cells. Findings suggest that these cell types may play a key role in the pathology and/or symptoms of Crohn’s disease.
The goal of this study is to generate a comprehensive map of intestinal stem cells and their cellular signaling pathways in healthy versus Crohn’s disease biopsies from children and adults, which together with functional analyses of these cells, will support development of new strategies to heal the epithelial barrier in patients with Crohn’s disease. This grant will also define how these cell types differ between children and adults.
Team: Christopher Lengner, Judith Kelsen, Kai Tan, Meenakshi Bewtra
The goal of this study is to characterize enterochromaffin cells and resident macrophages, two cell populations heavily involved in pain perception and immune regulation, from the terminal ileum and ascending colon of healthy individuals and Crohn’s disease patients to identify critical pathways and biomarkers involved in pain signaling and modulation of the immune response triggered by signals from the nervous system. This grant will also map specific cell types and states to their spatial locations within preserved tissue architecture to infer and characterize networks of cell-cell interactions in health and Crohn’s disease.
Team: Thierry Voet, Alejandro Sifrim, Marc Ferrante, Alexandre Denadai-Souza, Joakim Lundeberg
The following projects will pilot novel technologies that, if effective, will provide a new level of understanding of cellular behavior leading to intestinal inflammation.
The goal of this study is to evaluate and validate the utility of a new computational method (dropout-based co-occurrence) of single-cell gene expression analysis for identifying cell types in the context of healthy and Crohn’s disease gut tissue. This grant will also allow for deeper understanding of the cell types in the ileum and how these cells are altered in Crohn’s disease, in patients of different ages and from different ancestry groups.
Team: Subra Kugathasan, Greg Gibson, Eliver Ghosn
The goal of this study is to develop a novel technology that enables spatially resolved high-throughput gene expression profiling of tissue sections, enabling efficient study of cell-to-cell communication mechanisms and identification of aberrations in the intestinal tissue of Crohn’s disease patients compared to healthy individuals. This grant will also provide the research community with an easily accessible tool to map spatial locations of gene transcripts within each intestinal cell and tissue.
The goal of this study is to establish a sample preparation, imaging, and algorithmic pipeline to create at a micro- and nano-scale reconstructions of all the cells and their characteristics for the human enteric system and other associated tissues. This grant will provide proof of concept of the applicability of the synchrotron source X-rays and high-resolution microscopy imaging modalities to human intestinal samples and further offer a valuable anatomical map for the Gut Cell Atlas community.
The goal of this study is to develop the sphere-sequencing method to systematically identify and rank cellular interactions that occur in the healthy intestine and within the Crohn’s disease microenvironment. This grant will also enable efficient study of cell-to-cell communication mechanisms by characterizing the genes expressed in each cell, the profiling of ligand – receptor pairs on neighboring cells and the corresponding spatial location of various cells.