Inflammatory Bowel Disease (IBD) and its subtype Crohn?s disease (CD) arise due to a loss of tolerance to environmental antigens in genetically susceptible individuals. Longitudinal analysis has identified an inverse correlation between rates of communicable parasitic diseases and IBD, a phenomenon termed the ?hygiene hypothesis.? Tuft cells have recently been identified as a critical component for sensing and responding to parasitic infections. Our lab has recently identified that tuft cells may be heterogeneous in their lineage and function in microbiome response, and specific populations may be critical for mitigating inflammation in ileal inflammatory disease. Here, we propose innovative experimental and computational approaches to dissect the heterogeneity of tuft cell lineage, structure, and function as they relate to regulating immune responses in in vivo models of CD.
In aim 1, we will conduct single-cell sequencing, high resolution microscopy, and functional secretory assays to understand lineage-structure-function relationships in different tuft cell populations in mouse and enteroid models.
In aim 2, we utilize multiplex imaging, Cytometry Time-of-Flight (CyTOF), and cytokine profiling to probe the downstream tuft-type 2 response network by utilizing several chemical and genetic models of pathway ablation. Through our findings, we aim to make significant contributions to the current understanding of tuft cell biology and epithelial-microbiome crosstalk in the intestine. Ultimately, this research will allow us to diagnose, stratify, and, ultimately, treat patients with IBD and expand the pool of targets in this complex, multifactorial disease.

Public Health Relevance

Inflammatory bowel disease (IBD) is a complex, multifactorial condition that involves multiple aspects of the intestinal mucosa, microbiome, and immune system. We propose novel experimental and mechanistic studies to determine the role of heterogeneous chemosensory tuft cells in suppressing ileal inflammatory disease. These studies may provide a greater understanding of microbiome-host crosstalk in the intestine while also broadening the small pool of therapeutic targets in IBD.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Greenwel, Patricia
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Vanderbilt University Medical Center
Anatomy/Cell Biology
Schools of Medicine
United States
Zip Code
Chen, Bob; Herring, Charles A; Lau, Ken S (2018) pyNVR: Investigating factors affecting feature selection from scRNA-seq data for lineage reconstruction. Bioinformatics :
Liu, Qi; Herring, Charles A; Sheng, Quanhu et al. (2018) Quantitative assessment of cell population diversity in single-cell landscapes. PLoS Biol 16:e2006687
Herring, Charles A; Banerjee, Amrita; McKinley, Eliot T et al. (2018) Unsupervised Trajectory Analysis of Single-Cell RNA-Seq and Imaging Data Reveals Alternative Tuft Cell Origins in the Gut. Cell Syst 6:37-51.e9
Banerjee, Amrita; McKinley, Eliot T; von Moltke, Jakob et al. (2018) Interpreting heterogeneity in intestinal tuft cell structure and function. J Clin Invest 128:1711-1719
Herring, Charles A; Chen, Bob; McKinley, Eliot T et al. (2018) Single-Cell Computational Strategies for Lineage Reconstruction in Tissue Systems. Cell Mol Gastroenterol Hepatol 5:539-548
Simmons, Alan J; Lau, Ken S (2017) Deciphering tumor heterogeneity from FFPE tissues: Its promise and challenges. Mol Cell Oncol 4:e1260191
Kim, Sun Wook; Ehrman, Jonathan; Ahn, Mok-Ryeon et al. (2017) Shear stress induces noncanonical autophagy in intestinal epithelial monolayers. Mol Biol Cell 28:3043-3056
Almohazey, Dana; Lo, Yuan-Hung; Vossler, Claire V et al. (2017) The ErbB3 receptor tyrosine kinase negatively regulates Paneth cells by PI3K-dependent suppression of Atoh1. Cell Death Differ 24:855-865
McKinley, Eliot T; Sui, Yunxia; Al-Kofahi, Yousef et al. (2017) Optimized multiplex immunofluorescence single-cell analysis reveals tuft cell heterogeneity. JCI Insight 2:
Simmons, Alan J; Scurrah, CheriƩ R; McKinley, Eliot T et al. (2016) Impaired coordination between signaling pathways is revealed in human colorectal cancer using single-cell mass cytometry of archival tissue blocks. Sci Signal 9:rs11