Wiskott-Aldrich Syndrome (WAS) is an X-linked hematopoietic disease that is characterized by immunodeficiency, eczema, and microthrombocytopenia. While our understanding of the role of WASP in regulating actin assembly at the level of the Arp2/3 complex and thus, cell movement has increased dramatically, the cause of the microthrombocytopenia observed in human WAS patients remains a mystery. Information derived 40 years ago established that WASP deficient platelets have markedly diminished survival times in the circulation compared to normal platelets, and before bone marrow transplantation became the therapy of choice, splenectomy was widely practiced as a partial cure for the thrombocytopenia of these patients. Recent studies in WASP and WIP knockout mice mimic the rapid clearance times of human WAS platelets and reveal them to be the key underlying defect, as functional tests of WASP null platelets by different groups have shown them to activate, secrete, and spread equally well as normal platelets. We have developed a systematic approach to define clearance mechanisms and have, thus far, identified two previously unrecognized clearance pathways that detect altered carbohydrate presentation on the platelet vWf receptor.
Aim 1 will delineate the receptor-mediated pathway(s) that recognize WASP-/- and WIP-/- platelets using both quantitative in vitro and in vivo systems to measure platelet removal and to study WASP-/- and WIP-/- platelet-phagocyte interactions.
Aim 2 will determine how the loss of the either the WASP or WIP protein leads to altered actin dynamics in platelets. It will also determine whether the accumulated loss of N-WASP in platelets leads to cytoskeletal defects.
Aim 3 will complement these clearance studies and investigate if diminished platelet production contributes to the disease state of WASP- /- and WIP-/- animals. Therefore, the proposed studies will inform us as to the mechanism(s) that prematurely remove WAS null platelets from the circulation and generate fundamental knowledge as to processes that normally function to remove senile and damaged platelets, as well as lead to strategies that will enhance both platelet biogenesis and survival.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL059561-15
Application #
8380175
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
15
Fiscal Year
2012
Total Cost
$350,000
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
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
Shouval, Dror S; Biswas, Amlan; Kang, Yu Hui et al. (2016) Interleukin 1β Mediates Intestinal Inflammation in Mice and Patients With Interleukin 10 Receptor Deficiency. Gastroenterology 151:1100-1104
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
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
Grozovsky, Renata; Begonja, Antonija Jurak; Liu, Kaifeng et al. (2015) The Ashwell-Morell receptor regulates hepatic thrombopoietin production via JAK2-STAT3 signaling. Nat Med 21:47-54
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
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
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

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