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IMPAIRED INTEGRIN-DEPENDENT FUNCTION OF WASP-DEFICIENT PLATELETS

Award Number: R21HL091269
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/15/2009
PERIOD OF PERFORMANCE END DATE: 09/30/2012

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IMPAIRED INTEGRIN-DEPENDENT FUNCTION OF WASP-DEFICIENT PLATELETS - DESCRIPTION (provided by applicant): Patients with Wiskott-Aldrich syndrome (WAS) suffer from profound thrombocytopenia due to accelerated loss of intrinsically defective platelets. The exact mechanism of platelet loss is unknown. The affected gene product, WASP, is a blood cell cytoskeletal regulatory protein thought to reside in the cytoplasm of resting cells. We recently found that a pool of WASP (1/4 of the total) is localized in platelets in the membrane skeleton, the scaffold structure that underlies and stabilizes the lipid bilayer. On activating platelets with thrombin plus stirring, these WASP molecules behaved like genuine membrane skeletal proteins, undergoing activation by phosphorylation, altered partitioning to the cytoskeletal fraction and de- activation by proteolysis, changes that were abrogated in integrin aIIb¿3 deficient platelets and in normal platelets treated with integrin antagonist. The findings identify a pool of WASP in close juxtaposition to readily mobilized aIIb¿3 integrin molecules that participates in platelet cytoarchitectural re-arrangements requiring integrin outside-in signaling. The proposed R21 project will test the hypothesis that the central function of platelet WASP is regulating physiological responses that are dependent on integrin outside-in signaling. Because platelets of WAS patients have inherent limitations as a study model, a secondary goal of the project is to demonstrate that wasp-/- mouse platelets replicate the functional disease defects. We will test whether platelets of WAS patients and wasp-deficient mice are impaired (relative to respective control platelets) in adhesion and spreading on immobilized fibrinogen, a classic integrin outside-in dependent function, by the use of fluorescence microscopy and a photometric plate assay (aim 1a). We will also study platelet adhesion (to fibrinogen and to collagen) under flow conditions in a parallel plate perfusion system under venous shear rate and arteriolar shear rate (aim 1b). To advance the hypothesis that platelet WASP regulates integrin-dependent functions generally, platelets of patients and wasp-/- mice will be tested for aberrancies of additional functions known to require integrin outside in signaling. These are generation of procoagulant surfaces, to be assessed as exposed phosphatidylserine detected by binding of FITC-lactadherin (aim 2a), rebleeding in a mouse tail cut model to assess clot stabilization (aim 2b) and fibrin clot retraction (aim 2c). We anticipate that the results of this pilot project will (i) identify the central function of platelet WASP as regulation of integrin outside-in dependent physiological responses and (ii) establish a mouse model of the platelet disease defect and (iii) generate benchmark findings to support a hypothesis-driven RO1 project relying primarily on the mouse model to define the WASP signaling pathway in normal platelets and the molecular mechanism responsible for the patients' thrombocytopenia. PUBLIC HEALTH RELEVANCE: Patients with the Wiskott-Aldrich syndrome (WAS) inherit a defective gene called WASP, and as a result, the protein (also called WASP) is missing in their white blood cells and platelets. Platelets are the tiny cells required for blood clotting and wound healing. Due to an unknown defect, platelets of the patients are removed from the blood at an abnormally rapid rate, causing low platelet count (thrombocytopenia) and causing the patients to suffer from bleeding. The goal of this project is to identify the normal function of WASP in platelets and the cause of platelet loss in Wiskott-Aldrich patients.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2013 ( Subtotal = -$1,740 )
2013	2010	IMMUNE DISEASE INSTITUTE INC	800 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	000	2	1/30/2013	NON-COMPETING CONTINUATION	-$82,800
2013	2010	CHILDREN'S HOSPITAL CORPORATION	300 LONGWOOD AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	001	3	1/31/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$81,060
2013	2010	IMMUNE DISEASE INSTITUTE INC	800 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	003	2	2/20/2013	NON-COMPETING CONTINUATION	$16,713
2013	2010	CHILDREN'S HOSPITAL CORPORATION	300 LONGWOOD AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	002	3	2/20/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$16,713
														Subtotal = -$1,740

Issue Date FY: 2012 ( Subtotal = $0 )
2012	2010	IMMUNE DISEASE INSTITUTE INC	800 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	000	2	3/31/2012	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2010 ( Subtotal = $262,500 )
2010	2010	IMMUNE DISEASE INSTITUTE INC	800 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	000	2	4/30/2010	NON-COMPETING CONTINUATION	$262,500
														Subtotal = $262,500

Issue Date FY: 2009 ( Subtotal = $315,000 )
2009	2009	IMMUNE DISEASE INSTITUTE INC	800 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Cardiovascular Diseases Research	000	1	4/15/2009	NEW	$315,000
														Subtotal = $315,000

Grand Total All Awards = $575,760

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IMPAIRED INTEGRIN-DEPENDENT FUNCTION OF WASP-DEFICIENT PLATELETS

Award Number: R21HL091269

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/15/2009

PERIOD OF PERFORMANCE END DATE: 09/30/2012

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