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Novel mechanism mediating LPA-induced smooth muscle cell and vascular responses

Award Number: R01HL107466
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/08/2018
PERIOD OF PERFORMANCE END DATE: 06/30/2023

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Novel mechanism mediating LPA-induced smooth muscle cell and vascular responses - ABSTRACT Vascular smooth muscle cell (SMC) migration is a critical event in neointimal formation in the development of atherosclerosis and restenosis, Lysophosphatidic acid (LPA), is emerging as an important lipid mediator of the cellular events contributing to atherosclerosis. During the last grant period, using an LPA receptor knockout mouse model, we identified LPA receptor 1 as the major cell membrane receptor mediating LPA-induced SMC migration and neointimal formation. We also discovered the matricellular protein Cyr61 as the key molecule mediating LPA signaling, leading to SMC migration and neointimal formation. These findings established a new concept that Cyr61 bridges the LPA and integrin signaling pathways, leading to focal adhesion kinase (FAK) activation/SMC migration and neointimal formation. In this grant period, we propose to extend our investigation to identify the molecular mechanism by which LPA-Cyr61 induces SMC migration and the LPA-Cyr61 pathway contribution to atherogenesis. Very recently lineage-tracing studies reveal that a large portion of macrophage marker-positive cells in mouse and human atherosclerotic lesions are vascular SMC-derived cells, suggesting SMC migration/proliferation and differentiation play important roles in atherogenesis. Understanding of SMC migration mechanism will significantly contribute to understanding atherogenesis. To date, little is known about the nature and spatial-temporal regulation of the migration which drives kinases in the polarized leading edge of SMCs. Interestingly, our recent study revealed several exciting novel findings: 1) the novel pseudopodium- enriched atypical kinase 1 (PEAK1) activation is localized in the polarized leading edge of SMCs upon LPA treatment; 2) Cyr61 induces PEAK1 activation and 3) knockdown of PEAK1 blocked SMC migration, suggesting PEAK1 functions as a downstream key mediator of Cyr61, regulating SMC migration. Furthermore, we discovered that PEAK1 interacts with FAK, a key regulator of cell migration. We also observed that phosphorylated PEAK1 levels are highly increased in ApoE-/- atherosclerotic lesions. The function of the novel kinase PEAK1 in vascular disease is unknown. Our data suggest that PEAK1 is the novel mediator for FAK activation and SMC migration. Based on these new observations, we hypothesize that the LPA receptor- Cyr61-integrin-PEAK1-FAK axis mediates SMC cytoskeleton reorganization/migration and lesion formation in atherosclerosis. These hypotheses will be tested in the following specific aims. Aim 1: Determine the novel role of PEAK1/FAK interaction on the activation of the Src/PEAK1/FAK/Paxillin/Rac pathway and SMC migration. Aim 2: Dissect the novel mechanism by which Cyr61 interacts integrin-adhesion complex signaling, leading to membrane protrusion and cell migration using unique Cyr61 mutant SMCs from novel Cyr61dm/dm knock-in mice. Aim 3: Establish the roles of LPA receptors and Cyr61 in the development of atherosclerosis using our innovative LPA receptor/ApoE knockout, Cyr61dm/dm/ApoE-/- and SMC lineage tracing mouse models. The proposed studies are expected to identify novel targets for prevention and treatment of 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: 2024 ( Subtotal = -$3,205 )
2024	2020	TEXAS PERMIAN BASIN UNIV OF	4901 E UNIVERSITY BLVD # 4240	ODESSA	TX	79762	ECTOR	USA	Cardiovascular Diseases Research	000	8	4/23/2024	NON-COMPETING CONTINUATION	-$3,205
														Subtotal = -$3,205

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	UNIVERSITY OF TEXAS OF THE PERMIAN BASIN	4901 E UNIVERSITY BLVD	ODESSA	TX	79762	ECTOR	USA	Cardiovascular Diseases Research	000	8	6/7/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2020	UNIVERSITY OF TEXAS OF THE PERMIAN BASIN	4901 E UNIVERSITY BLVD	ODESSA	TX	79762	ECTOR	USA	Cardiovascular Diseases Research	000	8	4/21/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $460,967 )
2020	2020	UNIVERSITY OF TEXAS OF THE PERMIAN BASIN	4901 E UNIVERSITY BLVD	ODESSA	TX	79762	ECTOR	USA	Cardiovascular Diseases Research	000	8	7/16/2020	NON-COMPETING CONTINUATION	$460,967
														Subtotal = $460,967

Issue Date FY: 2019 ( Subtotal = $460,967 )
2019	2019	UNIVERSITY OF TEXAS OF THE PERMIAN BASIN	4901 E UNIVERSITY BLVD	ODESSA	TX	79762	ECTOR	USA	Cardiovascular Diseases Research	003	7	6/25/2019	NON-COMPETING CONTINUATION	$460,967
2019	2018	UNIVERSITY OF TEXAS OF THE PERMIAN BASIN	4901 E UNIVERSITY BLVD	ODESSA	TX	79762	ECTOR	USA	Cardiovascular Diseases Research	002	6	2/5/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2019	2018	UNIVERSITY OF TEXAS OF THE PERMIAN BASIN	4901 E UNIVERSITY BLVD	ODESSA	TX	79762	ECTOR	USA	Cardiovascular Diseases Research	000	6	10/26/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2019	2017	UNIVERSITY OF TENNESSEE	1331 CIR PARK DR	KNOXVILLE	TN	37916	KNOX	USA	Cardiovascular Diseases Research	001	5	2/5/2019	COMPETING CONTINUATION	$0
														Subtotal = $460,967

Issue Date FY: 2018 ( Subtotal = $497,717 )
2018	2018	UNIVERSITY OF TEXAS OF THE PERMIAN BASIN	4901 E UNIVERSITY BLVD	ODESSA	TX	79762	ECTOR	USA	Cardiovascular Diseases Research	003	6	8/10/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$270,792
2018	2018	UNIVERSITY OF TEXAS OF THE PERMIAN BASIN	4901 E UNIVERSITY BLVD	ODESSA	TX	79762	ECTOR	USA	Cardiovascular Diseases Research	001	6	8/8/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$497,717
2018	2017	UNIVERSITY OF TENNESSEE	1331 CIR PARK DR	KNOXVILLE	TN	37916	KNOX	USA	Cardiovascular Diseases Research	002	5	8/10/2018	COMPETING CONTINUATION	-$270,792
2018	2017	UNIVERSITY OF TENNESSEE	1331 CIR PARK DR	KNOXVILLE	TN	37916	KNOX	USA	Cardiovascular Diseases Research	000	5	8/8/2018	COMPETING CONTINUATION	$0
														Subtotal = $497,717

Issue Date FY: 2017 ( Subtotal = $460,967 )
2017	2017	UNIVERSITY OF TENNESSEE	1331 CIR PARK DR	KNOXVILLE	TN	37916	KNOX	USA	Cardiovascular Diseases Research	000	5	6/10/2017	COMPETING CONTINUATION	$460,967
2017	2014	UNIVERSITY OF TENNESSEE	1331 CIR PARK DR	KNOXVILLE	TN	37916	KNOX	USA	Cardiovascular Diseases Research	001	4	9/5/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $460,967

Issue Date FY: 2016 ( Subtotal = $0 )
2016	2014	UNIVERSITY OF TENNESSEE	WEST CUMBERLAND AVENUE, SW	KNOXVILLE	TN	37916	KNOX	USA	Cardiovascular Diseases Research	000	4	6/3/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2014 ( Subtotal = $357,700 )
2014	2014	UNIVERSITY OF TENNESSEE	WEST CUMBERLAND AVENUE, SW	KNOXVILLE	TN	37916	KNOX	USA	Cardiovascular Diseases Research	000	4	5/16/2014	NON-COMPETING CONTINUATION	$357,700
														Subtotal = $357,700

Issue Date FY: 2013 ( Subtotal = $347,480 )
2013	2013	UNIVERSITY OF TENNESSEE	WEST CUMBERLAND AVENUE, SW	KNOXVILLE	TN	37916	KNOX	USA	Cardiovascular Diseases Research	000	3	6/7/2013	NON-COMPETING CONTINUATION	$347,480
														Subtotal = $347,480

Issue Date FY: 2012 ( Subtotal = $357,500 )
2012	2012	UNIVERSITY OF TENNESSEE	WEST CUMBERLAND AVENUE, SW	KNOXVILLE	TN	37916	KNOX	USA	Cardiovascular Diseases Research	001	2	5/7/2012	NON-COMPETING CONTINUATION	$365,000
2012	2011	UNIVERSITY OF TENNESSEE	WEST CUMBERLAND AVENUE, SW	KNOXVILLE	TN	37916	KNOX	USA	Cardiovascular Diseases Research	000	1	5/4/2012	NEW	-$7,500
														Subtotal = $357,500

Issue Date FY: 2011 ( Subtotal = $372,500 )
2011	2011	UNIVERSITY OF TENNESSEE	WEST CUMBERLAND AVENUE, SW	KNOXVILLE	TN	37916	KNOX	USA	Cardiovascular Diseases Research	000	1	6/13/2011	NEW	$372,500
														Subtotal = $372,500

Grand Total All Awards = $3,312,593

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Novel mechanism mediating LPA-induced smooth muscle cell and vascular responses

Award Number: R01HL107466

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/08/2018

PERIOD OF PERFORMANCE END DATE: 06/30/2023

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