Advancements in human genetics now poise the field to illuminate the pathophysiology of inflammatory pathologies and infectious disease. Although the mechanisms of immune-mediated tissue homeostasis are incompletely understood, genetic analyses of inflammatory disease and primary immunodeficiencies have implicated shared proteins and pathways representing key immune checkpoints. Efforts to map the genetic architecture of inflammatory bowel disease (IBD) have been particularly fruitful, leading to the discovery of ATG16L1 T300A, which revealed the importance of autophagy in innate immunity. We have since shown that the ATG16L1 T300A allele conspires with environmental triggers to induce several cell type-specific phenotypes resulting in tissue dys-homeostasis and predisposition to inflammatory pathology. Thus, mechanistic characterization of a pathogenic autophagy variant has provided fundamental insights into mucosal immunity. The focus of this application is to understand how genetic perturbation of autophagy checkpoints impacts inflammation control and tissue homeostasis in the context of mucosal immunity. Towards this end, we propose to: (1) Define the role of autophagy checkpoints in intestinal inflammation, (2) Identify the molecular mechanisms by which autophagy controls antigen presentation and tissue homeostasis, and (3) Perform a comprehensive genetic dissection of the Inflammation-Autophagy link.

Public Health Relevance

With autoimmune disease incidence on the rise and the emergence of drug-resisant bacteria, there is a pressing need to identify mechanisms of immune regulation. The study of human genetics promises to broaden our understanding of disease risk and pathological drivers of disease; however, there exist many limitations in connecting genetic loci to pathogenic traits. The focus of this application is to understand how inherited perturbation of autophagy checkpoints impacts inflammation control and tissue homeostasis in the context of mucosal immunity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK097485-05
Application #
9596439
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Perrin, Peter J
Project Start
2013-01-01
Project End
2022-04-30
Budget Start
2018-07-01
Budget End
2019-04-30
Support Year
5
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
Graham, Daniel B; Jasso, Guadalupe J; Mok, Amanda et al. (2018) Nitric Oxide Engages an Anti-inflammatory Feedback Loop Mediated by Peroxiredoxin 5 in Phagocytes. Cell Rep 24:838-850
Jijon, H B; Suarez-Lopez, L; Diaz, O E et al. (2018) Intestinal epithelial cell-specific RAR? depletion results in aberrant epithelial cell homeostasis and underdeveloped immune system. Mucosal Immunol 11:703-715
Franco, Luis H; Nair, Vidhya R; Scharn, Caitlyn R et al. (2017) The Ubiquitin Ligase Smurf1 Functions in Selective Autophagy of Mycobacterium tuberculosis and Anti-tuberculous Host Defense. Cell Host Microbe 21:59-72
Bel, Shai; Pendse, Mihir; Wang, Yuhao et al. (2017) Paneth cells secrete lysozyme via secretory autophagy during bacterial infection of the intestine. Science 357:1047-1052
Goodwin, Jonathan M; Dowdle, William E; DeJesus, Rowena et al. (2017) Autophagy-Independent Lysosomal Targeting Regulated by ULK1/2-FIP200 and ATG9. Cell Rep 20:2341-2356
Haber, Adam L; Biton, Moshe; Rogel, Noga et al. (2017) A single-cell survey of the small intestinal epithelium. Nature 551:333-339
Murano, Tatsuro; Najibi, Mehran; Paulus, Geraldine L C et al. (2017) Transcription factor TFEB cell-autonomously modulates susceptibility to intestinal epithelial cell injury in vivo. Sci Rep 7:13938
Lassen, Kara G; McKenzie, Craig I; Mari, Muriel et al. (2016) Genetic Coding Variant in GPR65 Alters Lysosomal pH and Links Lysosomal Dysfunction with Colitis Risk. Immunity 44:1392-405
Graham, Daniel B; Lefkovith, Ariel; Deelen, Patrick et al. (2016) TMEM258 Is a Component of the Oligosaccharyltransferase Complex Controlling ER Stress and Intestinal Inflammation. Cell Rep 17:2955-2965
DeJesus, Rowena; Moretti, Francesca; McAllister, Gregory et al. (2016) Functional CRISPR screening identifies the ufmylation pathway as a regulator of SQSTM1/p62. Elife 5:

Showing the most recent 10 out of 30 publications