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Integration of single-cell imaging and multi-omics sequencing to study EC mechano-pathophysiology

Award Number: R01HL121365
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/20/2013
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Integration of single-cell imaging and multi-omics sequencing to study EC mechano-pathophysiology - Summary Epigenetic regulation of vascular functions has been found to play crucial roles in cardiovascular diseases. Vascular endothelial cells (ECs), which are exposed to different flow patterns, regulate vascular homeostasis. Differential epigenetic changes, e.g. histone modifications, caused by different flow patterns regulate EC gene expression profile and hence functional consequences. The coupling of histone phosphorylation, methylation, and acetylation have recently been identified to regulate gene expressions through the distinct chromatin remodeling complexes, which would alter the consequential phenotypic outcome. However, there is a paucity of study in the flow-regulation of histone modifications in vascular cells. We hypothesize that the coupling among epigenetic histone phosphorylation, methylation, and acetylation may serve as a transducing mechanism to regulate EC gene expressions under different patterns of flows. We will develop a directed evolution strategy for the systematic optimization and tuning of FRET biosensors with distinct colors to simultaneously monitor different histone modifications with high sensitivity and specificity. These biosensors will be used to track multiple histone modifications simultaneously in the same live cell and unravel the evolving multiplex landscape of histone modifications under different flows. We will further employ the endonuclease-deficient Cas9 (dCas9), small guide RNAs (sgRNAs) and split FPs to track the dynamics of histone modifications at the specific loci of EC phenotype marker genes. Our epigenetic manipulation system will then be employed to modulate epigenetics at these specific loci and determine their effects on gene expressions and consequent cellular functions in single live cells under different flows. The identified epigenetic profiles will then be modulated in vivo, and the consequent gene expression and phenotypic outcome examined. Four specific aims are proposed: 1) Develop and optimize FRET biosensors to visualize the dynamic histone modifications in single cells, 2) Unravel the spatiotemporal coupling of histone phosphorylation-methylation-acetylation in regulating EC functions under different flows, 3) Establish the roles of locus-specific histone modifications in regulating EC gene expression under flows, 4) Elucidate the effect of histone modifications on gene expression and lesion formation in vivo. The simultaneous tracking of the spatiotemporal dynamics of histone modifications in the nucleus in conjunction with cell proliferation and inflammation in a single live cell will allow the elucidation of the spatiotemporal transducing mechanism in regulating epigenetic modulations and pathophysiological consequences upon the exposure of ECs to hemodynamic cues. The mechanistic insights obtained should allow us to identify the potential molecular targets and facilitate the design of pharmaceutical interventions for pathologic processes. As such, the project should have transformative impact in the field of vascular mechanobiology, particularly related to the molecular regulations of cell cycle and inflammation in mediating the development of atherosclerosis.


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 = $583,656 )
2024	2024	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90089	LOS ANGELES	USA	Cardiovascular Diseases Research	002	11	7/23/2024	NON-COMPETING CONTINUATION	$583,656
2024	2023	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Cardiovascular Diseases Research	001	10	10/19/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$317,814
2024	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cardiovascular Diseases Research	000	9	10/19/2023	COMPETING CONTINUATION	-$317,814
														Subtotal = $583,656

Issue Date FY: 2023 ( Subtotal = $623,789 )
2023	2023	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST	LOS ANGELES	CA	90089	LOS ANGELES	USA	Cardiovascular Diseases Research	002	10	6/26/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$623,789
2023	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Cardiovascular Diseases Research	001	9	6/24/2023	COMPETING CONTINUATION	$0
2023	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Cardiovascular Diseases Research	000	8	6/16/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $623,789

Issue Date FY: 2022 ( Subtotal = $789,998 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cardiovascular Diseases Research	001	9	5/26/2022	COMPETING CONTINUATION	$789,998
2022	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cardiovascular Diseases Research	000	8	5/26/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $789,998

Issue Date FY: 2021 ( Subtotal = $554,730 )
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cardiovascular Diseases Research	000	8	12/11/2020	NON-COMPETING CONTINUATION	$499,257
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cardiovascular Diseases Research	001	8	5/18/2021	NON-COMPETING CONTINUATION	$55,473
														Subtotal = $554,730

Issue Date FY: 2020 ( Subtotal = $571,837 )
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cardiovascular Diseases Research	001	7	1/24/2020	NON-COMPETING CONTINUATION	$28,591
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Cardiovascular Diseases Research	000	7	11/27/2019	NON-COMPETING CONTINUATION	$543,246
														Subtotal = $571,837

Issue Date FY: 2019 ( Subtotal = $591,159 )
2019	2019	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Cardiovascular Diseases Research	000	6	1/18/2019	NON-COMPETING CONTINUATION	$591,159
														Subtotal = $591,159

Issue Date FY: 2018 ( Subtotal = $604,500 )
2018	2018	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Cardiovascular Diseases Research	000	5	12/15/2017	COMPETING CONTINUATION	$604,500
2018	2018	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Cardiovascular Diseases Research	002	5	3/26/2018	COMPETING CONTINUATION	$36
2018	2017	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Cardiovascular Diseases Research	001	4	3/26/2018	NON-COMPETING CONTINUATION	-$36
														Subtotal = $604,500

Issue Date FY: 2017 ( Subtotal = $643,526 )
2017	2017	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Cardiovascular Diseases Research	000	4	11/25/2016	NON-COMPETING CONTINUATION	$643,526
														Subtotal = $643,526

Issue Date FY: 2016 ( Subtotal = $657,904 )
2016	2016	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Cardiovascular Diseases Research	001	3	2/23/2016	NON-COMPETING CONTINUATION	$9,869
2016	2016	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Cardiovascular Diseases Research	000	3	12/8/2015	NON-COMPETING CONTINUATION	$648,035
														Subtotal = $657,904

Issue Date FY: 2015 ( Subtotal = $659,249 )
2015	2015	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Cardiovascular Diseases Research	002	2	2/23/2015	NON-COMPETING CONTINUATION	$51,159
2015	2015	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Cardiovascular Diseases Research	000	2	11/19/2014	NON-COMPETING CONTINUATION	$541,682
2015	2015	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Cardiovascular Diseases Research	001	2	12/15/2014	SUPPLEMENT FOR EXPANSION	$66,408
														Subtotal = $659,249

Issue Date FY: 2014 ( Subtotal = $618,450 )
2014	2014	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Cardiovascular Diseases Research	001	1	3/11/2014	NEW	$61,845
2014	2014	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Cardiovascular Diseases Research	000	1	12/20/2013	NEW	$556,605
														Subtotal = $618,450

Grand Total All Awards = $6,898,798

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Integration of single-cell imaging and multi-omics sequencing to study EC mechano-pathophysiology

Award Number: R01HL121365

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/20/2013

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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