Emerging evidence suggests a central role for dendritic cells (DCs) in inducing immune tolerance. Our recent research has provided critical new insights into the molecular mechanisms that ?program? DCs to induce tolerogenic responses. In particular, we have observed an unappreciated intersection between the ancient nutrient-sensing pathway, involving the amino acid sensing molecule GCN2, and control of inflammation in the gut. Given the central role of GCN2 as a sensor of amino acid starvation, we explored its? potential role in the intestine, and observed its remarkable effects on modulating the functions of intestinal DCs and epithelial cells to control inflammation in the gut. In this context the goal of the research proposed here is to determine the mechanisms by which GCN2 and this stress response pathway regulate gut inflammation.
Aim 1 : To determine the mechanism by which the GCN2-eIF2? pathway regulates intestinal immunity and inflammation. Our preliminary data demonstrates that GCN2-/- mice display enhanced susceptibility to intestinal inflammation and strikingly enhanced Th17 responses. Here we will explore the effects of conditional ablation of GCN2 expression in DCs versus intestinal epithelial cells, and whether these effects are dependent on down the downstream kinase eIF2?.
Aim 2 : To determine the cause and consequence of excess reactive oxygen species (ROS) production in GCN2 deficient mice. Our preliminary data show that GCN2-/- mice have enhanced intestinal inflammation and elevated levels of ROS in gut DCs and epithelial cells. In this aim we propose to determine the cause and consequence of excess ROS production in the GCN2-/- mice.
Aim 3 : To determine the mechanism by which GCN2 suppresses inflammasome activation. Finally, our preliminary data demonstrates increased inflammasome activation in gut DCs and epithelial cells in GCN2-/- mice. In this aim, we will determine whether this inflammasome activation is essential for enhanced intestinal inflammation and Th17 responses. The successful completion of these aims will provide new mechanistic insights into how this stress response pathway controls intestinal inflammation, and provide new therapeutic strategies against autoimmunity.

Public Health Relevance

A central property of the immune system is its ability to maintain immune tolerance and avoid auto-reactivity against self-antigens. Recent research in our lab has revealed an unappreciated role for an ancient amino acid sensing pathway in the control of immunity and inflammation in the gut. The present proposal is aimed at deciphering the molecular mechanisms underlying this regulatory step.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
7R37DK057665-20
Application #
9542942
Study Section
Special Emphasis Panel (NSS)
Program Officer
Spain, Lisa M
Project Start
2015-09-01
Project End
2020-08-31
Budget Start
2017-09-03
Budget End
2018-08-31
Support Year
20
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Stanford University
Department
Pathology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94304
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