The following is a revised version of RO1 AG013983-22 entitled """"""""B Cells and Autoimmunity"""""""", which has been reduced in scope to pursue research that can be accomplished in two years rather than the originally proposed five years. The previous application, which received a priority score at the 12.7 percentile, proposed to address three specific aims. To reduce scope we eliminated two aims and will pursue studies originally proposed in the remaining aim entitled """"""""Does the SHIP-1/Dok-1 pathway mediate anergic B cell hyporesponsiveness to antigen, CXCL12 and BAFF, and, if so, how? Studies will test the concept of a mobile PtdIns3,4,5P3 scavenger complex (mPsc) that consists of SHIP-1 and Dok-1, and functions to hydrolyze PtdIns3,4,5P3 needed for signaling."""""""" We have chosen to pursue this aim for multiple reasons. Studies proposed in this aim are the most involved of the three, requiring the most man-hours and reagents. They easily represent 40 percent of the original scope and budget, and thus are appropriate for the limited two-year funding period. Furthermore, it is these studies that we are best prepared to undertake immediately since all reagents and models are in place. Studies proposed in the deleted aims will require significant mouse breeding, and thus only limited progress could be made in two years. Finally, we believe that the studies proposed in retained aim are the most exciting and important scientifically, and thus will make the greatest contribution to the field.
Autoimmune diseases afflict 14.7 to 23.5 million people in the United States alone. The proposed research will contribute significantly to our understanding of the role of B cells in the development of autoimmunity, and may lead to discovery of useful biomarkers and novel therapies for this family of diseases.
|Hinman, Rochelle M; Smith, Mia J; Cambier, John C (2014) B cells and type 1 diabetes ...in mice and men. Immunol Lett 160:128-32|
|O'Neill, Shannon K; Getahun, Andrew; Gauld, Stephen B et al. (2011) Monophosphorylation of CD79a and CD79b ITAM motifs initiates a SHIP-1 phosphatase-mediated inhibitory signaling cascade required for B cell anergy. Immunity 35:746-56|
|Yarkoni, Yuval; Cambier, John C (2011) Differential STIM1 expression in T and B cell subsets suggests a role in determining antigen receptor signal amplitude. Mol Immunol 48:1851-8|
|Yarkoni, Yuval; Getahun, Andrew; Cambier, John C (2010) Molecular underpinning of B-cell anergy. Immunol Rev 237:249-63|
|Chan, Marcia A; Gigliotti, Nicole M; Matangkasombut, Ponpan et al. (2010) CD23-mediated cell signaling in human B cells differs from signaling in cells of the monocytic lineage. Clin Immunol 137:330-6|
|Waterman, Paul M; Cambier, John C (2010) The conundrum of inhibitory signaling by ITAM-containing immunoreceptors: potential molecular mechanisms. FEBS Lett 584:4878-82|
|Cambier, John C; Getahun, Andy (2010) B cell activation versus anergy; the antigen receptor as a molecular switch. Immunol Lett 128:6-7|
|Getahun, Andrew; O'Neill, Shannon K; Cambier, John C (2009) Establishing anergy as a bona fide in vivo mechanism of B cell tolerance. J Immunol 183:5439-41|
|O'Neill, Shannon K; Liu, Edwin; Cambier, John C (2009) Change you can B(cell)eive in: recent progress confirms a critical role for B cells in type 1 diabetes. Curr Opin Endocrinol Diabetes Obes 16:293-8|
|Crowley, Jenni E; Stadanlick, Jason E; Cambier, John C et al. (2009) FcgammaRIIB signals inhibit BLyS signaling and BCR-mediated BLyS receptor up-regulation. Blood 113:1464-73|
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