Abstract

The proposed program project is based on our central hypothesis that Wiskott-Aldrich syndrome protein (WASP), its homologue N-WASP, and its partner WASP interactive protein (WIP), are involved in cytoskeletal re-organization and gene induction upon activation of blood cells. Toward this end we targeted the genes encoding all these proteins by homologous recombination. We plan to exploit these """"""""knock-outs"""""""" to elucidate the pathway(s) from cell surface receptors to cytoskeletal re-organization in T cells, B cells and platelets. The proposal consists of four projects and two cores. Project 1 (R. Geha) seeks to understand the overlapping and non-overlapping roles of WASP, WIP and the WASP-WIP complex in T cell activation and cytoskeletal reorganization. Project 2 (S. Snapper and F. Alt) and Project 3 (L. Notarangelo) will dissect the role of WASP, N-WASP and WIP in T and B cell function respectively. Project 4 (John Hartwig) will examine the role of WASP, N-WASP and WIP in maintaining platelet homeostasis. Core A will administer the program. Core B will provide genetically engineered mice and generate monoclonal antibodies for all four projects.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL059561-15
Application #
8321062
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Mitchell, Phyllis
Project Start
1997-09-30
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
15
Fiscal Year
2012
Total Cost
$1,790,387
Indirect Cost
$436,278

  Institution

Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115

  Publications

Garber, John J; Mallick, Emily M; Scanlon, Karen M et al. (2018) Attaching-and-Effacing Pathogens Exploit Junction Regulatory Activities of N-WASP and SNX9 to Disrupt the Intestinal Barrier. Cell Mol Gastroenterol Hepatol 5:273-288
Vardi, Iddo; Barel, Ortal; Sperber, Michal et al. (2018) Genetic and Structural Analysis of a SKIV2L Mutation Causing Tricho-hepato-enteric Syndrome. Dig Dis Sci 63:1192-1199
Li, Jian; Shouval, Dror S; Doty, Andria L et al. (2017) Increased Mucosal IL-22 Production of an IL-10RA Mutation Patient Following Anakin Treatment Suggests Further Mechanism for Mucosal Healing. J Clin Immunol 37:104-107
Lexmond, Willem S; Goettel, Jeremy A; Lyons, Jonathan J et al. (2016) FOXP3+ Tregs require WASP to restrain Th2-mediated food allergy. J Clin Invest 126:4030-4044
Baptista, Marisa A P; Keszei, Marton; Oliveira, Mariana et al. (2016) Deletion of Wiskott-Aldrich syndrome protein triggers Rac2 activity and increased cross-presentation by dendritic cells. Nat Commun 7:12175
Volpi, Stefano; Santori, Elettra; Abernethy, Katrina et al. (2016) N-WASP is required for B-cell-mediated autoimmunity in Wiskott-Aldrich syndrome. Blood 127:216-20
Moran, Christopher J; Klein, Christoph; Muise, Aleixo M et al. (2015) Very early-onset inflammatory bowel disease: gaining insight through focused discovery. Inflamm Bowel Dis 21:1166-75
Crestani, Elena; Volpi, Stefano; Candotti, Fabio et al. (2015) Broad spectrum of autoantibodies in patients with Wiskott-Aldrich syndrome and X-linked thrombocytopenia. J Allergy Clin Immunol 136:1401-4.e1-3
Kolhatkar, Nikita S; Brahmandam, Archana; Thouvenel, Christopher D et al. (2015) Altered BCR and TLR signals promote enhanced positive selection of autoreactive transitional B cells in Wiskott-Aldrich syndrome. J Exp Med 212:1663-77
Gerasimcik, Natalija; Dahlberg, Carin I M; Baptista, Marisa A P et al. (2015) The Rho GTPase Cdc42 Is Essential for the Activation and Function of Mature B Cells. J Immunol 194:4750-8

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