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.

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
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Ramesh, Narayanaswamy; Massaad, Michel J; Kumar, Lalit et al. (2014) Binding of the WASP/N-WASP-interacting protein WIP to actin regulates focal adhesion assembly and adhesion. Mol Cell Biol 34:2600-10
Olszak, Torsten; Neves, Joana F; Dowds, C Marie et al. (2014) Protective mucosal immunity mediated by epithelial CD1d and IL-10. Nature 509:497-502
Shouval, Dror S; Ouahed, Jodie; Biswas, Amlan et al. (2014) Interleukin 10 receptor signaling: master regulator of intestinal mucosal homeostasis in mice and humans. Adv Immunol 122:177-210
Wurbel, Marc-André; Le Bras, Severine; Ibourk, Mouna et al. (2014) CCL25/CCR9 interactions are not essential for colitis development but are required for innate immune cell protection from chronic experimental murine colitis. Inflamm Bowel Dis 20:1165-76
Bender, Markus; Falet, Hervé (2014) Post-translational arginylation as a novel regulator of platelet function. Haematologica 99:402-4
Benchimol, Eric I; Mack, David R; Nguyen, Geoffrey C et al. (2014) Incidence, outcomes, and health services burden of very early onset inflammatory bowel disease. Gastroenterology 147:803-813.e7; quiz e14-5
Avitzur, Yaron; Guo, Conghui; Mastropaolo, Lucas A et al. (2014) Mutations in tetratricopeptide repeat domain 7A result in a severe form of very early onset inflammatory bowel disease. Gastroenterology 146:1028-39
Massaad, Michel J; Oyoshi, Michiko K; Kane, Jennifer et al. (2014) Binding of WIP to actin is essential for T cell actin cytoskeleton integrity and tissue homing. Mol Cell Biol 34:4343-54
Mallick, Emily M; Garber, John J; Vanguri, Vijay K et al. (2014) The ability of an attaching and effacing pathogen to trigger localized actin assembly contributes to virulence by promoting mucosal attachment. Cell Microbiol 16:1405-24
Shouval, Dror S; Biswas, Amlan; Goettel, Jeremy A et al. (2014) Interleukin-10 receptor signaling in innate immune cells regulates mucosal immune tolerance and anti-inflammatory macrophage function. Immunity 40:706-19

Showing the most recent 10 out of 85 publications