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Endogenous suppression of integrin signaling

Award Number: R01HL119374
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2013
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Endogenous suppression of integrin signaling - Cardiovascular disease (CVD) is the number one killer of mankind. Most CVDs are associated with atherosclerosis and thrombosis. It is well documented that platelets are the initiators of both atherosclerosis and thrombosis. Platelets are maintained in resting state in the circulation by endogenous negative regulators to avoid unintentional activation. During vascular injury, pro- stimulatory signals override anti-stimulatory signals to achieve rapid platelet activation. Lot of research is focused on pro-stimulatory signals while little is known about negative regulators. We have shown that JAM-A is an endogenous suppressor of platelet activation. Ablation of JAM-A confers an augmentation of in vivo thrombosis. However, upon platelet activation what happens to JAM-A is not known. We hypothesize that JAM-A forms a dimer upon dissociation from the integrin complex and support junctional assembly at the platelet–platelet junctions through the activation of Rap1. This R01 proposal is focused on delineating the role of JAM-A in initiating platelet-platelet junction formation, and thus preventing blood loss through the wound. Accordingly, three Specific Aims have been proposed. Specific Aim 1 will test the hypothesis that platelet JAM-A associates with the integrin through CD9, a tetraspanin, by forming a multi- protein complex in a PDZ-domain-dependent manner. We will use biochemical, mutational and genetic approaches to identify the components of this complex. Specific Aim 2 will test the hypothesis that upon platelet activation JAM-A dimerizes and assembles Rap1-activating complex to achieve Rap1 activation during outside-in signaling. We will use biochemical, mutational and genetic approaches to delineate the molecular mechanism that regulate JAM-A- dependent Rap1 activation. Specific Aim 3 will test the hypothesis that JAM-A is responsible in recruiting junctional proteins at the platelet-platelet contacts to assemble functional junctions. We will use genetically modified cells and mice to evaluate the role of JAM-A and other known junctional proteins in regulating permeability of hemostatic plug using in vitro and in vivo assays. Successful completion of this proposal will help to understand the role of junctional adhesion molecules in hemostasis and to develop therapeutic interventions for thrombosis associated diseases such as atherosclerosis, MI, and stroke.


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: 2026 ( Subtotal = $0 )
2026	2022	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Blood Diseases and Resources Research	000	9	12/22/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Blood Diseases and Resources Research	000	9	7/3/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $580,289 )
2022	2022	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Blood Diseases and Resources Research	000	9	6/3/2022	NON-COMPETING CONTINUATION	$580,289
														Subtotal = $580,289

Issue Date FY: 2021 ( Subtotal = $562,301 )
2021	2021	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Blood Diseases and Resources Research	000	8	6/17/2021	NON-COMPETING CONTINUATION	$562,301
														Subtotal = $562,301

Issue Date FY: 2020 ( Subtotal = $562,610 )
2020	2020	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Blood Diseases and Resources Research	000	7	6/15/2020	NON-COMPETING CONTINUATION	$562,610
														Subtotal = $562,610

Issue Date FY: 2019 ( Subtotal = $576,904 )
2019	2019	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Blood Diseases and Resources Research	000	6	8/14/2019	COMPETING CONTINUATION	$576,904
														Subtotal = $576,904

Issue Date FY: 2018 ( Subtotal = $0 )
2018	2016	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Blood Diseases and Resources Research	000	5	8/29/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2016 ( Subtotal = $390,000 )
2016	2016	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Blood Diseases and Resources Research	000	5	5/23/2016	NON-COMPETING CONTINUATION	$390,000
														Subtotal = $390,000

Issue Date FY: 2015 ( Subtotal = $384,017 )
2015	2015	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Blood Diseases and Resources Research	002	4	5/15/2015	NON-COMPETING CONTINUATION	$384,017
2015	2014	UNIVERSITY OF DELAWARE	210 HULLIHEN HALL	NEWARK	DE	19716	NEW CASTLE	USA	Blood Diseases and Resources Research	000	2	3/17/2015	NON-COMPETING CONTINUATION	-$97,276
2015	2014	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Blood Diseases and Resources Research	001	3	3/17/2015	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$97,276
														Subtotal = $384,017

Issue Date FY: 2014 ( Subtotal = $382,200 )
2014	2014	UNIVERSITY OF DELAWARE	210 HULLIHEN HALL	NEWARK	DE	19716	NEW CASTLE	USA	Blood Diseases and Resources Research	000	2	5/30/2014	NON-COMPETING CONTINUATION	$382,200
														Subtotal = $382,200

Issue Date FY: 2013 ( Subtotal = $369,098 )
2013	2013	UNIVERSITY OF DELAWARE	210 HULLIHEN HALL	NEWARK	DE	19716	NEW CASTLE	USA	Blood Diseases and Resources Research	000	1	7/23/2013	NEW	$369,098
														Subtotal = $369,098

Grand Total All Awards = $3,807,419

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Endogenous suppression of integrin signaling

Award Number: R01HL119374

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2013

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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