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Shear Stress Activation of Endothelial Membrane Function

Award Number: R37HL040696
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/1988
PERIOD OF PERFORMANCE END DATE: 06/30/2020

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Shear Stress Activation of Endothelial Membrane Function - Project Abstract Vascular mechanotransduction has long been recognized as mediating physiological processes such as flow-dependent dilation and pathological processes such as the localization of lesions in atherosclerosis. There is a consensus that hemodynamic forces represent two distinct biomechanical stimuli; that is, while unidirectional laminar fluid shear is atheroprotective, rapidly changing and/or reverse fluid shear stress (coupled with low average shear) is atherogenic. The overall goal of this application is to determine the molecular basis of mechanochemical signal transduction and the endothelium's ability to discriminate between these two biomechanical stimuli. We have already demonstrated that the atherogenic/inflammatory hemodynamic signaling originates from a macromolecular complex assembled around PECAM-1 at the endothelial cell-cell junction. One of the objectives of this application is to define the organization of the macromolecular complex located at the endothelial cell-cell junction and elucidate its mechanism of activation. The second objective is to investigate the hypothesis that the structural geometry of the junction regulates the sensitivity of the macromolecular complex to rapidly changing shear and confers the ability to discriminate between unidirectional and oscillatory/reverse flow. This project will use an entirely integrative approach using molecular biology, cell biology and biochemistry, vital cell imaging, and cell biomechanics. In particular, the specific aims are: 1) To investigate the interaction of PECAM-1 with VE-cadherin and VEGFR2 at the molecular level and the regulation of mechanochemical signaling through this interaction; 2) Determine the role of junctional GPCRs and G-proteins in mechanochemical signaling and their regulation by PECAM-1; 3) Characterize the geometry of the cell-cell junction by measuring its angle of inclination in in vivo and flow-adapted in vitro endothelium; and 4) Determine whether junctional inclination regulates endothelial response to reverse and oscillatory flow. The understanding of the molecular and structural mechanisms by which the endothelium senses oscillatory and reverse flow is crucial for the development of targeted therapies for flow-induced vascular inflammation and atherogenesis.


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: 2021 ( Subtotal = $0 )
2021	2018	LA JOLLA BIOENGINEERING INSTITUTE	505 COAST BOULEVARD SOUTH 411	LA JOLLA	CA	92037	SAN DIEGO	USA	Cardiovascular Diseases Research	000	32	9/17/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $568,700 )
2018	2018	LA JOLLA BIOENGINEERING INSTITUTE	505 COAST BOULEVARD SOUTH 411	LA JOLLA	CA	92037	SAN DIEGO	USA	Cardiovascular Diseases Research	000	32	6/29/2018	NON-COMPETING CONTINUATION	$568,700
														Subtotal = $568,700

Issue Date FY: 2017 ( Subtotal = $568,700 )
2017	2017	LA JOLLA BIOENGINEERING INSTITUTE	505 COAST BOULEVARD SOUTH 411	LA JOLLA	CA	92037	SAN DIEGO	USA	Cardiovascular Diseases Research	000	31	6/21/2017	NON-COMPETING CONTINUATION	$568,700
														Subtotal = $568,700

Issue Date FY: 2016 ( Subtotal = $568,700 )
2016	2016	LA JOLLA BIOENGINEERING INSTITUTE	505 COAST BOULEVARD SOUTH	LA JOLLA	CA	92037	SAN DIEGO	USA	Cardiovascular Diseases Research	000	30	6/17/2016	NON-COMPETING CONTINUATION	$568,700
														Subtotal = $568,700

Issue Date FY: 2015 ( Subtotal = $722,402 )
2015	2015	LA JOLLA BIOENGINEERING INSTITUTE	505 COAST BOULEVARD SOUTH	LA JOLLA	CA	92037	SAN DIEGO	USA	Cardiovascular Diseases Research	000	29	6/8/2015	NON-COMPETING CONTINUATION	$722,402
														Subtotal = $722,402

Issue Date FY: 2014 ( Subtotal = $733,404 )
2014	2014	LA JOLLA BIOENGINEERING INSTITUTE	505 COAST BOULEVARD SOUTH	LA JOLLA	CA	92037	SAN DIEGO	USA	Cardiovascular Diseases Research	001	28	8/9/2014	EXTENSION WITH OR WITHOUT FUNDS	$568,700
2014	2014	LA JOLLA BIOENGINEERING INSTITUTE	505 COAST BOULEVARD SOUTH	LA JOLLA	CA	92037	SAN DIEGO	USA	Cardiovascular Diseases Research	002	28	9/6/2014	SUPPLEMENT FOR EXPANSION	$164,704
2014	2013	LA JOLLA BIOENGINEERING INSTITUTE	505 COAST BOULEVARD SOUTH	LA JOLLA	CA	92037	SAN DIEGO	USA	Cardiovascular Diseases Research	000	27	8/8/2014	NON-COMPETING CONTINUATION	$0
														Subtotal = $733,404

Issue Date FY: 2013 ( Subtotal = $602,120 )
2013	2013	LA JOLLA BIOENGINEERING INSTITUTE	505 COAST BOULEVARD SOUTH	LA JOLLA	CA	92037	SAN DIEGO	USA	Cardiovascular Diseases Research	000	27	6/26/2013	NON-COMPETING CONTINUATION	$602,120
														Subtotal = $602,120

Issue Date FY: 2012 ( Subtotal = $617,154 )
2012	2012	LA JOLLA BIOENGINEERING INSTITUTE	505 COAST BOULEVARD SOUTH	LA JOLLA	CA	92037	SAN DIEGO	USA	Cardiovascular Diseases Research	000	26	6/14/2012	NON-COMPETING CONTINUATION	$467,775
2012	2012	LA JOLLA BIOENGINEERING INSTITUTE	505 COAST BOULEVARD SOUTH	LA JOLLA	CA	92037	SAN DIEGO	USA	Cardiovascular Diseases Research	001	26	9/7/2012	SUPPLEMENT FOR EXPANSION	$149,379
														Subtotal = $617,154

Issue Date FY: 2011 ( Subtotal = $472,500 )
2011	2011	LA JOLLA BIOENGINEERING INSTITUTE	505 COAST BOULEVARD SOUTH	LA JOLLA	CA	92037	SAN DIEGO	USA	Cardiovascular Diseases Research	000	25	6/28/2011	NON-COMPETING CONTINUATION	$472,500
														Subtotal = $472,500

Issue Date FY: 2010 ( Subtotal = $472,500 )
2010	2010	LA JOLLA BIOENGINEERING INSTITUTE	505 COAST BOULEVARD SOUTH	LA JOLLA	CA	92037	SAN DIEGO	USA	Cardiovascular Diseases Research	002	24	7/13/2010	NON-COMPETING CONTINUATION	$472,500
2010	2009	LA JOLLA BIOENGINEERING INSTITUTE	505 COAST BOULEVARD SOUTH	LA JOLLA	CA	92037	SAN DIEGO	USA	Cardiovascular Diseases Research	001	23	11/9/2009	COMPETING CONTINUATION	$0
2010	2009	LA JOLLA BIOENGINEERING INSTITUTE	505 COAST BOULEVARD SOUTH	LA JOLLA	CA	92037	SAN DIEGO	USA	Cardiovascular Diseases Research	000	23	11/9/2009	COMPETING CONTINUATION	$0
														Subtotal = $472,500

Grand Total All Awards = $5,326,180

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Shear Stress Activation of Endothelial Membrane Function

Award Number: R37HL040696

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/1988

PERIOD OF PERFORMANCE END DATE: 06/30/2020

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