Advances in prevention and treatment of autoimmune diseases, allergy, transplant rejection, and infection depend upon identifying key regulatory genes and biochemical pathways in the immune system that can be used to enhance diagnostic specificity and as targets for new drugs or vaccines. This project will take advantage of the recently completed sequencing of the human and mouse genome and a new approach of genome-wide mutagenesis to produce new animal models of immunological disease, to identify key regulatory genes, and to elucidate cellular and molecular pathways underpinning immune regulation. A C57BL/6 transgenic mouse model will be used as the starting point for genome-wide mutagenesis, using the chemical supermutagen ENU to alter the function of tens of thousands of genes in the mammalian genome in a highly parallel method. A consortium of investigators will develop and validate screening tests to identify mice with altered immune regulation, and then define the mutant gene, molecular pathways, and cellular processes revealed by each new mouse strain. The consortium will establish, characterize and disseminate many new mouse strains with mutations that reveal critical genes and pathways for immunity versus tolerance decisions: regulating development, inactivation and activation of different subsets of T cells, B cells, and NK cells; counterbalancing signals from activating and inhibitory receptors; guiding leukocyte migration and microenvironmental interactions; and establishing response differences in isotype-switched memory cells. The results of this work will identify promising targets and strategies for improving the success of therapeutic tolerance in autoimmunity, allergy, and transplantation, and for enhancing immunity to infectious diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI052127-03
Application #
6761776
Study Section
Allergy & Clinical Immunology-1 (AITC)
Program Officer
Deckhut Augustine, Alison M
Project Start
2002-09-15
Project End
2007-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
3
Fiscal Year
2004
Total Cost
$1,653,757
Indirect Cost
Name
Australian National University
Department
Type
DUNS #
756669727
City
Canberra
State
Country
Australia
Zip Code
0200
Siggs, Owen M; Miosge, Lisa A; Daley, Stephen R et al. (2015) Quantitative reduction of the TCR adapter protein SLP-76 unbalances immunity and immune regulation. J Immunol 194:2587-95
Siggs, Owen M; Yates, Adèle L; Schlenner, Susan et al. (2014) A ZAP-70 kinase domain variant prevents thymocyte-positive selection despite signalling CD69 induction. Immunology 141:587-95
Han, Brenda Y; Wu, Shuang; Foo, Chuan-Sheng et al. (2014) Zinc finger protein Zfp335 is required for the formation of the naïve T cell compartment. Elife 3:
Bergmann, Hannes; Yabas, Mehmet; Short, Alanna et al. (2013) B cell survival, surface BCR and BAFFR expression, CD74 metabolism, and CD8- dendritic cells require the intramembrane endopeptidase SPPL2A. J Exp Med 210:31-40
Daley, Stephen R; Hu, Daniel Y; Goodnow, Christopher C (2013) Helios marks strongly autoreactive CD4+ T cells in two major waves of thymic deletion distinguished by induction of PD-1 or NF-?B. J Exp Med 210:269-85
Teh, C E; Horikawa, K; Arnold, C N et al. (2013) Heterozygous mis-sense mutations in Prkcb as a critical determinant of anti-polysaccharide antibody formation. Genes Immun 14:223-33
Andrews, T D; Sjollema, G; Goodnow, C C (2013) Understanding the immunological impact of the human mutation explosion. Trends Immunol 34:99-106
Daley, Stephen R; Coakley, Kristen M; Hu, Daniel Y et al. (2013) Rasgrp1 mutation increases naive T-cell CD44 expression and drives mTOR-dependent accumulation of Helios? T cells and autoantibodies. Elife 2:e01020
Enders, Anselm; Stankovic, Sanda; Teh, Charis et al. (2012) ZBTB7B (Th-POK) regulates the development of IL-17-producing CD1d-restricted mouse NKT cells. J Immunol 189:5240-9
Andrews, T D; Whittle, B; Field, M A et al. (2012) Massively parallel sequencing of the mouse exome to accurately identify rare, induced mutations: an immediate source for thousands of new mouse models. Open Biol 2:120061

Showing the most recent 10 out of 20 publications