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The role of VWF and platelets in BBB alterations associated with hypoxia

Award Number: F32NS073245
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 06/01/2011
PERIOD OF PERFORMANCE END DATE: 05/31/2014

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The role of VWF and platelets in BBB alterations associated with hypoxia - DESCRIPTION (provided by applicant): Hypoxia followed by reoxygenation is commonly used as a model to investigate pathology associated with ischemia/reperfusion as the latter condition is present in several disease states including stroke. In animal models, hypoxia followed by reoxygenation has been shown to cause tight junction protein abnormalities, increased BBB paracellular permeability and edema however, a complete mechanism leading to these pathologies is still undefined. von Willebrand Factor (VWF) is a glycoprotein that is only synthesized by endothelial cells and megakaryocytes. While it is known that VWF is expressed abundantly by cerebral endothelial cells (CECs), very little is known about the role of VWF in endothelial biology, particularly, in regulation of the BBB under stressful conditions. Data we have generated demonstrate that VWF-deficient mice have significantly less BBB permeability than wild type in a model of generalized hypoxia/reoxygenation. VWF is a major ligand for platelets during endothelial activation and preliminary data we have gathered support a role for platelets in survival of exposure to hypoxia. Platelets are best known for their role in hemostasis and inflammation and the primary ligand for platelet binding to the endothelium and exposed subendothelium is VWF. Platelets can activate endothelium but are also activated by inflamed endothelium. Data supporting alteration of platelet number and function after exposure to hypoxia have been documented. However, studies have yielded conflicting results leaving much room for advancements in this field. Intriguingly, a role for platelets as potentiators of increased paracellular permeability in human brain endothelial cell cultures has been documented and recent literature suggests a role for platelets in various CNS diseases involving the BBB. The role of VWF and platelets in BBB biology is understudied and warrants further investigation, thus our overall objective is to determine the extent VWF and platelets promote BBB permeability under stressful conditions. To accomplish this, we will use a model of generalized normobaric hypoxia followed by reoxygenation. In our first aim, we propose to examine the role of plasma vs. subendothelial VWF in increased BBB permeability associated with generalized hypoxia/reoxygenation. Secondly, we will determine the extent that platelet interactions with VWF and the endothelium lead to increased BBB permeability. We propose to accomplish these aims using knock out mouse technology, BBB permeability assays, confocal microscopy, platelet-depletion studies and tight junction protein assays. The studies outlined in this proposal aim to further our understanding of how a glycoprotein expressed by brain microvasculature interacts with a cell type of hematopoietic lineage to influence the BBB during hypoxia and thus are directly relevant to the mission of NINDS, specifically the neural environment division.


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: 2014 ( Subtotal = -$44,955 )
2014	2013	CHILDREN'S HOSPITAL CORPORATION	300 LONGWOOD AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	11/6/2013	NON-COMPETING CONTINUATION	-$44,955
														Subtotal = -$44,955

Issue Date FY: 2013 ( Subtotal = $10,715 )
2013	2013	CHILDREN'S HOSPITAL CORPORATION	300 LONGWOOD AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	4	4/16/2013	NON-COMPETING CONTINUATION	$55,670
2013	2013	CHILDREN'S HOSPITAL CORPORATION	300 LONGWOOD AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	4	11/6/2013	NON-COMPETING CONTINUATION	-$44,955
2013	2012	CHILDREN'S HOSPITAL CORPORATION	300 LONGWOOD AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	3/18/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$30,728
2013	2012	IMMUNE DISEASE INSTITUTE INC	800 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	3/18/2013	NON-COMPETING CONTINUATION	-$30,728
														Subtotal = $10,715

Issue Date FY: 2012 ( Subtotal = $53,942 )
2012	2012	IMMUNE DISEASE INSTITUTE INC	800 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	5/16/2012	NON-COMPETING CONTINUATION	$53,942
														Subtotal = $53,942

Issue Date FY: 2011 ( Subtotal = $51,326 )
2011	2011	IMMUNE DISEASE INSTITUTE INC	800 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	5/31/2011	NEW	$51,326
2011	2011	IMMUNE DISEASE INSTITUTE INC	800 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	5/31/2011	NEW	$0
														Subtotal = $51,326

Grand Total All Awards = $71,028

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The role of VWF and platelets in BBB alterations associated with hypoxia

Award Number: F32NS073245

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 06/01/2011

PERIOD OF PERFORMANCE END DATE: 05/31/2014

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