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MECHANOSENSITIVITY OF CELL MEMBRANES: ROLE OF LIPID-PROTEIN INTERACTIONS

Award Number: R01HL086943
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/04/2007
PERIOD OF PERFORMANCE END DATE: 03/31/2013

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MECHANOSENSITIVITY OF CELL MEMBRANES: ROLE OF LIPID-PROTEIN INTERACTIONS - DESCRIPTION (provided by applicant): Hemodynamic shear stress stimulates number of intracellular events that both regulate vessel structure and also influence development of vascular pathologies. The precise molecular mechanisms by which endothelial cells transduce this mechanical stimulus into intracellular biochemical response have not been established yet. The central hypothesis is that the plasma membrane of endothelial cell acts as a mechanosensitive element; i.e. changes in physical properties of the membrane under mechanical stress can regulate activity of membrane proteins coupled to intracellular signaling pathways. To test this hypothesis, we will use an integrative approach that combines time-resolved fluorescence microscopy, biochemistry, cell biology, and membrane micromechanics. Our preliminary experiments show for the first time that (1) when exposed to mechanical forces, membrane lateral fluidity and hydration levels change and (2) that increases in membrane tension lead to activation of bradykinin G protein coupled receptor (GPCR). The proposed research addresses the following questions: (1) which physical properties of the lipid bilayer change in response to mechanical perturbation, (2) which of these changes has a clear link to function of membrane-associated proteins such as GPCRs, G-proteins and endothelial nitric oxide synthase (eNOS), and can mediate mechanochemical signal transduction, and (3) what are the specific mechanisms leading to mechanically induced activation of GPCR receptors, eNOS and G-proteins by shear stress. We will use state-of-the-art picosecond time-resolved fluorescence, single molecule and fluorescence correlation spectroscopy techniques to investigate in detail what happens to the physical properties of the lipid bilayer membrane at the molecular level under mechanical stress and how these changes are coupled to mechanochemical signal transduction via direct activation of the membrane associated proteins such as GPCR's and modulation of signal amplification cascades through G- proteins. Specifically we propose that mechanically-induced changes in certain membrane properties such as thickness, lateral fluidity, polarity, membrane free volume and/or trans-membrane lateral force profile are able to initiate and regulate conformational changes responsible for experimentally observed response of GPCR and G protein signal transduction pathways and eNOS activation. If successful it will provide the mechanistic basis on how endothelial cells sense flow in both normal physiology and in vascular disease.


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: 2012 ( Subtotal = $104,664 )
2012	2012	LA JOLLA BIOENGINEERING INSTITUTE	505 COAST BOULEVARD SOUTH	LA JOLLA	CA	92037	SAN DIEGO	USA	Cardiovascular Diseases Research	000	5	3/8/2012	SUPPLEMENT FOR EXPANSION	$104,664
														Subtotal = $104,664

Issue Date FY: 2011 ( Subtotal = $530,046 )
2011	2011	LA JOLLA BIOENGINEERING INSTITUTE	505 COAST BOULEVARD SOUTH	LA JOLLA	CA	92037	SAN DIEGO	USA	Cardiovascular Diseases Research	000	5	3/7/2011	NON-COMPETING CONTINUATION	$530,046
2011	2009	LA JOLLA BIOENGINEERING INSTITUTE	505 COAST BOULEVARD SOUTH	LA JOLLA	CA	92037	SAN DIEGO	USA	Trans-NIH Recovery Act Research Support	001	3	6/9/2011	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $530,046

Issue Date FY: 2010 ( Subtotal = $487,535 )
2010	2010	LA JOLLA BIOENGINEERING INSTITUTE	505 COAST BOULEVARD SOUTH	LA JOLLA	CA	92037	SAN DIEGO	USA	Cardiovascular Diseases Research	001	4	8/26/2010	SUPPLEMENT FOR EXPANSION	$61,385
2010	2010	LA JOLLA BIOENGINEERING INSTITUTE	505 COAST BOULEVARD SOUTH	LA JOLLA	CA	92037	SAN DIEGO	USA	Cardiovascular Diseases Research	000	4	3/5/2010	NON-COMPETING CONTINUATION	$426,150
														Subtotal = $487,535

Issue Date FY: 2009 ( Subtotal = $808,214 )
2009	2009	LA JOLLA BIOENGINEERING INSTITUTE	505 COAST BOULEVARD SOUTH	LA JOLLA	CA	92037	SAN DIEGO	USA	Trans-NIH Recovery Act Research Support	001	3	7/15/2009	SUPPLEMENT FOR EXPANSION	$382,064
2009	2009	LA JOLLA BIOENGINEERING INSTITUTE	505 COAST BOULEVARD SOUTH	LA JOLLA	CA	92037	SAN DIEGO	USA	Cardiovascular Diseases Research	000	3	3/27/2009	NON-COMPETING CONTINUATION	$426,150
														Subtotal = $808,214

Issue Date FY: 2008 ( Subtotal = $426,150 )
2008	2008	LA JOLLA BIOENGINEERING INSTITUTE	505 COAST BOULEVARD SOUTH	LA JOLLA	CA	92037	SAN DIEGO	USA	Cardiovascular Diseases Research	000	2	3/19/2008	NON-COMPETING CONTINUATION	$426,150
														Subtotal = $426,150

Issue Date FY: 2007 ( Subtotal = $378,800 )
2007	2007	LA JOLLA BIOENGINEERING INSTITUTE	505 COAST BOULEVARD SOUTH	LA JOLLA	CA	92037	SAN DIEGO	USA	Cardiovascular Diseases Research	000	1	4/4/2007	NEW	$378,800
														Subtotal = $378,800

Grand Total All Awards = $2,735,409

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MECHANOSENSITIVITY OF CELL MEMBRANES: ROLE OF LIPID-PROTEIN INTERACTIONS

Award Number: R01HL086943

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/04/2007

PERIOD OF PERFORMANCE END DATE: 03/31/2013

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