zE ABSTRACT This is a renewal RO01l aplliicatiionto study receptor editing, which is a mechanismof immune tolerance involving secondary immunoglobulin (lIg) light chain rearrangements that change B cell receptor (BCR) specificity. Collectively, receptor editing mechanisms promote tolerance by reprogrammiingBcelspecifiiciity,,rattherrthanthroughclolonall deletion. The long term goal of these studies is to understandthe mechanismsthat controltthesiginalilninganadndexeexceuctuiotionnooffrerecceptotorrediitiing. '-"""""""" 0)a) = Ox) Non autoreactive BCRs expressedby developingBcelspromottedevelolopmentatall progressionand the cessation of V(D)J recombination(positive selection),whereas autoreactive receptors promote ongoing L-chain gene recombinationandediting.These divergent biological outcomes relyon the qualityofthesiignallsgenerattedbyan innocuous vs autoreactive BCRs. In this applicationwe proposetostudyGSK3a, a protein kinase regulatedby BCR signalingthatappearstopllayarolleiinprromotitning receptor editing. These studies will involveanalysisofcellllliine,,mouseknockoutsts,,andB cell overexpression modelsto obtain acomprehensiiveviewoftherolelesoffGSK3cai in receptorediting.. -CD ='a -TM a)N (n0 -,cam The SpecificAim of this proposalis as folows: . 3 3 v Aim 1. To determineiifandhowGSK3aregulalatetesrreceptotorreditiitning.. The studieswil alsoaddrestherellattedquesttiionoffhowandwhytthecloloselylyrrelalateted protein GSK3P is poorly activated by BCR signaling in immature B cells. ARRA Response:2 R01 A1033608-16A1 ARRA Response: 2 ROl A1033608-16A1 F-- protein GSK3$3 is poorly activated by BCR signaling in immature B cells. L-'

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI033608-17
Application #
7835661
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Nasseri, M Faraz
Project Start
1992-12-01
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2012-04-30
Support Year
17
Fiscal Year
2010
Total Cost
$474,750
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Aoki-Ota, Miyo; Torkamani, Ali; Ota, Takayuki et al. (2012) Skewed primary Ig? repertoire and V-J joining in C57BL/6 mice: implications for recombination accessibility and receptor editing. J Immunol 188:2305-15
Tiegs, Susan L; Russell, David M; Nemazee, David (2011) Receptor editing in self-reactive bone marrow B cells. The Journal of Experimental Medicine. 1993. 177: 1009-1020. J Immunol 186:1313-24
Ota, Miyo; Duong, Bao H; Torkamani, Ali et al. (2010) Regulation of the B cell receptor repertoire and self-reactivity by BAFF. J Immunol 185:4128-36
Beck, Kristina; Peak, Mandy M; Ota, Takayuki et al. (2009) Distinct roles for E12 and E47 in B cell specification and the sequential rearrangement of immunoglobulin light chain loci. J Exp Med 206:2271-84
Huber, Christoph; Martensson, Annica; Bokoch, Gary M et al. (2008) FGD2, a CDC42-specific exchange factor expressed by antigen-presenting cells, localizes to early endosomes and active membrane ruffles. J Biol Chem 283:34002-12
Vela, Jose Luis; Ait-Azzouzene, Djemel; Duong, Bao Hoa et al. (2008) Rearrangement of mouse immunoglobulin kappa deleting element recombining sequence promotes immune tolerance and lambda B cell production. Immunity 28:161-70
Verkoczy, Laurent; Duong, Bao; Skog, Patrick et al. (2007) Basal B cell receptor-directed phosphatidylinositol 3-kinase signaling turns off RAGs and promotes B cell-positive selection. J Immunol 178:6332-41
Verkoczy, Laurent; Ait-Azzouzene, Djemel; Skog, Patrick et al. (2005) A role for nuclear factor kappa B/rel transcription factors in the regulation of the recombinase activator genes. Immunity 22:519-31
Ait-Azzouzene, Djemel; Skog, Patrick; Retter, Marc et al. (2004) Tolerance-induced receptor selection: scope, sensitivity, locus specificity, and relationship to lymphocyte-positive selection. Immunol Rev 197:219-30
Verkoczy, Laurent K; Martensson, Annica S; Nemazee, David (2004) The scope of receptor editing and its association with autoimmunity. Curr Opin Immunol 16:808-14

Showing the most recent 10 out of 20 publications