The gut serves as a nexus that connects and integrates organ systems throughout the body, with far-reaching consequences in health and disease. The biological function of the gut as an organ is the result of complex interactions between dynamic and heterogeneous cell types. Any pathological insult to the gut, such as barrier breach or infection, must be met with a response that is appropriate and proportional to the insult, such that homeostasis is re-established. In this application, we propose novel single-cell genomic approaches to decipher heterogeneous cellular responses to inflammatory challenge. Through a series of functional genetics studies, we aim to elucidate the molecular basis of mucosal immunity in the context of pathological inflammation. Towards this end, we propose the following specific aims:
Aim 1. Comprehensively define all cell lineages and dynamic functional states in intestinal inflammation.
Aim 2. Delineate intercellular communication networks that coordinate intestinal inflammation.
Aim 3. Identify disease modifier pathways in human biopsies and integrate with intercellular communication networks.

Public Health Relevance

The gut mucosa serves as a central hub wherein the host interacts with its environment (diet and commensals), relays information throughout the body (neuronal, endocrine systems), and responds in a dynamic manner (immunity versus tolerance). The host's ability to coordinate communication networks between disparate cell types in the mucosa impacts several human disease states including infectious disease, autoimmunity, and cancer. In this proposal, we will implement and innovate comprehensive approaches in single cell profiling to elucidate the molecular basis of immunity in the context of mucosal homeostasis and inflammatory pathology.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
High Impact Research and Research Infrastructure Programs (RC2)
Project #
5RC2DK114784-02
Application #
9532828
Study Section
Special Emphasis Panel (ZDK1)
Program Officer
Perrin, Peter J
Project Start
2017-08-01
Project End
2022-07-31
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Broad Institute, Inc.
Department
Type
DUNS #
623544785
City
Cambridge
State
MA
Country
United States
Zip Code
Biton, Moshe; Haber, Adam L; Rogel, Noga et al. (2018) T Helper Cell Cytokines Modulate Intestinal Stem Cell Renewal and Differentiation. Cell 175:1307-1320.e22
Haber, Adam L; Biton, Moshe; Rogel, Noga et al. (2017) A single-cell survey of the small intestinal epithelium. Nature 551:333-339