The central theme of the Program Project Is focused on mechanisms that determine innate and acquired immune responses in the intestinal mucosa to enteric microbes and microbial products, and the consequent mucosal protective immune and inflammatory responses. The four interrelated research projects specifically address the regulation of communication between epithelial cells and dendritic cells, and between dendritic cells and T cells, which takes place during mucosal homeostasis and protective immunity. Model enteric pathogens are used to probe mucosal cellular responses in novel in vivo and in vitro murine model systems. The program brings together experienced investigators from the Departments of Medicine, Pathology, and Neurosciences and the UCSD campus based La Jolla Institute for Allergy and Immunology. The investigators have a record of significant expertise in cellular and molecular mucosal immunology, mucosal inflammation, cell signaling and microbial pathogenesis, and a record of collaborative interactions. Research Unit 1 investigates the regulation of innate mucosal immune responses by dendritic cells (DC) and epithelial cells in the colon and small intestine. Unit 1 uses an attaching and effacing lesion-inducing enteric pathogen and rotavirus to probe the host response, and the mechanisms by which granulocyte-macrophage colony stimulating factor determines the outcome of enteric infection. Research Unit 2 investigates intestinal mucosal responses that determine immune defenses against minimally invasive enteric pathogens, using Giardia as a model protozoan pathogen that elicits strong protective immunity in the absence of mucosal inflammation. Research Unit 3 investigates how mucosal adjuvants override the tolerance-inducing effects of T regulatory cells and provoke effector T cell immune responses, with a focus on cholera toxin and Th17 differentiation in vitro and in vivo. Research Unit 4, which is new to the Program with the renewal application, investigates mechanisms by which retinoids determine the balance between normal mucosal homeostasis and protective immunity through their activity on DC and T cells. The research projects are supported by four Cores: a Mouse Model Core, a Histopathology Core, an Imaging and Cell Sorting Core and an Administrative Core.

Public Health Relevance

The intestinal mucosa is a major site of interaction between the host and enteric enteric pathogens that cause diarrheal illness, morbidity and death among millions worldwide each year. These studies will elucidate mechanisms and pathways that determine the host responses to infection with enteric microbes and microbial products. We anticipate our research will result in the identification of cellular and molecular targets that can be used and manipulated to achieve more effective host protective immunity to enteric infections through pharmacological, molecular, cellular and vaccine interventions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK035108-27
Application #
8294915
Study Section
Special Emphasis Panel (ZDK1-GRB-9 (M1))
Program Officer
Hamilton, Frank A
Project Start
1997-04-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
27
Fiscal Year
2012
Total Cost
$1,485,974
Indirect Cost
$502,163
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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