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ENABLING STRUCTURAL STUDIES OF FORCE ACTIVATED ADHESION COMPLEXES

Award Number: F32HL099167
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 01/01/2011
PERIOD OF PERFORMANCE END DATE: 07/31/2012

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ENABLING STRUCTURAL STUDIES OF FORCE ACTIVATED ADHESION COMPLEXES - DESCRIPTION (provided by applicant): The broad, long-term objective of the proposed research is to develop a method to enable crystal structure studies of adhesion proteins in their force activated, extended-state conformation. Atomic level knowledge of the physiological (or pathological) state of adhesion complexes should increase our understanding of the regulation of force activated protein-ligand complexes and enable more effective drugs to treat and prevent disease. Specifically, the applicant will study the interaction between the A1-domain of Von Willebrand Factor (VWF-A1) and platelet glycoprotein GPIb a-domain (GPIba). This interaction is activated by shear forces in hemodynamic flow and is important for hemostasis. We hypothesize the existence of a force-activated, extended-state complex between VWF-A1 and GPIba. Without a priori knowledge of the extended-state structure, obtaining crystal structures of these complexes is currently impossible since there is no physiologically meaningful way to apply force to a protein crystal. Therefore, we propose to develop a method to identify mutations that stabilize the extended-state complex with the purpose of obtaining these elusive crystal structures in the absence of force. The specific aims of the research are to (1) Find mutants with enhanced affinity for both VWF-A1 and GPIba. Since it is not obvious what mutations need to be made to stabilize the extended-state, the applicant will use a combination of random and focused mutagenesis coupled with yeast surface display to screen for high affinity binders (i.e., activated). The applicant will then (2) Combine mutations in VWF-A1 and GPIba to uncover potential synergistic effects. Next, the applicant will (3) Characterize the binding affinity and kinetics of the putative extended-state mutant pairs using flow cytometry and surface plasmon resonance. (4) The mutations' effects on adhesion dynamics and mechanical stability will be studied in parallel plate flow chamber studies. Last, the applicant will (5) Crystallize the extended-state complex for structural elucidation and comparison to wild-type and Von Willebrand Disease mutants. PUBLIC HEALTH RELEVANCE: Von Willebrand Factor plays a crucial role in the body's ability to cease bleeding from wounds. In order to better understand this process, and diseases where wounds cannot cease bleeding, we seek molecular level knowledge of how Von Willebrand Factor performs its hemostatic role. This understanding may lead to more effective treatments for bleeding disorders.


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 = -$18,475 )
2013	2012	IMMUNE DISEASE INSTITUTE INC	800 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	000	2	12/11/2012	NON-COMPETING CONTINUATION	-$18,475
														Subtotal = -$18,475

Issue Date FY: 2012 ( Subtotal = $52,190 )
2012	2012	IMMUNE DISEASE INSTITUTE INC	800 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	001	2	2/10/2012	NON-COMPETING CONTINUATION	$1,716
2012	2012	IMMUNE DISEASE INSTITUTE INC	800 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	000	2	11/17/2011	NON-COMPETING CONTINUATION	$50,474
														Subtotal = $52,190

Issue Date FY: 2010 ( Subtotal = $47,606 )
2010	2010	IMMUNE DISEASE INSTITUTE INC	800 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	000	1	9/10/2010	NEW	$47,606
														Subtotal = $47,606

Grand Total All Awards = $81,321

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ENABLING STRUCTURAL STUDIES OF FORCE ACTIVATED ADHESION COMPLEXES

Award Number: F32HL099167

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 01/01/2011

PERIOD OF PERFORMANCE END DATE: 07/31/2012

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