Dendritic cells (DCs) are innate immune cells that regulate both immune homeostasis as well as antigen driven immune responses. The functions of DCs are highly regulated by signals initiated by Toll-like receptors (TLRs). Consequently, intracellular molecules that regulate TLR signaling pathways are pivotal for regulating host immune responses. We have recently found that A20 is a ubiquitin modifying enzyme that restricts toll-like receptor (TLR) induced signals. We are studying the roles of A20 expression in DCs in regulating immune homeostasis and responses. To accomplish this, we have generated two strains of gene targeted mice: one that disrupts the A20 gene in all cells and one in which a "floxed" allele of A20 has been targeted to the endogenous A20 locus. We have interbred the "floxed" mice with a novel strain of CD11-Cre transgenic mouse line that expresses Cre enzyme with high selectivity and specificity in DCs. These compound A20flox/flox CD11c-Cre mice will thus provide us with a very powerful and novel reagent for studying the role of A20 expression in DCs in regulating immune homeostasis and immune responses. We propose to use these A20flox/flox CD11-cre compound mice, as well as cells derived from both strains of mice, to determine how A20 expression in DCs regulates their responses to TLR ligands in vitro and in vivo.
The first aim will focus upon understanding the cell biology and biochemistry underlying A20's roles in regulating TLR signaling in DCs, and will elucidate the cell-autonomous functions of DCs that are regulated by A20.
The second aim will utilize A20flox/flox CD11c-Cre mice to determine how A20 expression in DCs regulates their homeostasis and activation in vivo.
This second aim will also interrogate how A20 expression in DCs regulates peripheral tolerance and immune responses and prevents autoimmunity. These studies should teach us a great deal about how dendritic cells are normally regulated, and how they may play a major role in preventing autoimmunity and regulating immune responses. They may also provide novel therapeutic targets for controlling inflammation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI078869-05
Application #
8381251
Study Section
Special Emphasis Panel (ZAI1-MP-I)
Project Start
Project End
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$374,609
Indirect Cost
$130,911
Name
University of California San Francisco
Department
Type
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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Lamagna, Chrystelle; Hu, Yongmei; DeFranco, Anthony L et al. (2014) B cell-specific loss of Lyn kinase leads to autoimmunity. J Immunol 192:919-28
Hammer, Gianna Elena; Ma, Averil (2013) Molecular control of steady-state dendritic cell maturation and immune homeostasis. Annu Rev Immunol 31:743-91
Molofsky, Ari B; Nussbaum, Jesse C; Liang, Hong-Erh et al. (2013) Innate lymphoid type 2 cells sustain visceral adipose tissue eosinophils and alternatively activated macrophages. J Exp Med 210:535-49
Lamagna, Chrystelle; Scapini, Patrizia; van Ziffle, Jessica A et al. (2013) Hyperactivated MyD88 signaling in dendritic cells, through specific deletion of Lyn kinase, causes severe autoimmunity and inflammation. Proc Natl Acad Sci U S A 110:E3311-20
Graham, Michelle T; Abram, Clare L; Hu, Yongmei et al. (2013) Expression of the TEL-Syk fusion protein in hematopoietic stem cells leads to rapidly fatal myelofibrosis in mice. PLoS One 8:e77542

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