Abstract

: The proposed program project is based on our central hypothesis that novel signaling pathways are involved in cytoskeletal re-organization upon activation of blood cells. Toward this end we targeted certain relevant genes by homologous recombination: Wiskott-Aldrich syndrome protein (WASP); N-WASP, WASP interactive protein (WIP), Vav 1 and Vav 3, Cdc42 and Rac. We now plan to exploit these """"""""knock-out"""""""": to elucidate the pathway(s) from cell surface receptors to cytoskeletal re-organization. The proposal consists of four projects and three cores. Project 1 seeks to understand the overlapping and non-overlapping roles of WASP and N-WASP by identifying their functional domains as well as those of the homologous protein WAVE-2 and to determine the roles of the GTPases, Cdc42 and Rac1, in lymphocyte development and function. Project 2 is devoted to a study of the function of WIP in the control of WASP and N-WASP activation for actin polymerization. Dr. Brugge studies the effect of Vav 1, 2 and 3 on chemotaxis of monocytes and neutrophils. Dr. Rao will study the relationship of calcium flux in lymphocytes to the function of the cytoskeletal pathways in anergy as well as T cell activation. Core A will administer the program.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL059561-06
Application #
6560508
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Harvath, Liana
Project Start
1997-09-30
Project End
2007-11-30
Budget Start
2002-12-16
Budget End
2003-11-30
Support Year
6
Fiscal Year
2003
Total Cost
$1,576,931
Indirect Cost

  Institution

Name
Immune Disease Institute, Inc.
Department
Type
DUNS #
059709394
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
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
Begonja, Antonija Jurak; Pluthero, Fred G; Suphamungmee, Worawit et al. (2015) FlnA binding to PACSIN2 F-BAR domain regulates membrane tubulation in megakaryocytes and platelets. Blood 126:80-8
Goettel, Jeremy A; Biswas, Subhabrata; Lexmond, Willem S et al. (2015) Fatal autoimmunity in mice reconstituted with human hematopoietic stem cells encoding defective FOXP3. Blood 125:3886-95

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