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Dynamics of cardiac nuclei in heart disease

Award Number: R01HL105699
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2011
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Dynamics of cardiac nuclei in heart disease - PROJECT SUMMARY/ABSTRACT Epigenetic processes have been implicated in control of cardiac development and in the incidence and progression of disease. Heart failure in particular has been shown to involve the actions of chromatin remodeling enzymes and to proceed by temporal reorganization of histone modifications and gene expression. The scientific premise of this application is that understanding the principles of chromatin structure-function, including the roles of specific molecular targets such as the linker histone H1 family, is key to re-engineering healthy transcriptomes in the setting of disease. Based on preliminary data implicating its role in fibroblast phenotype, we will mechanistically investigate the role of linker histone H1.0 in chromatin organization, using gain- and loss-of- function approaches in cells and in vivo. We hypothesize that precise structural orientation of the genome is underpinned by cell type-specific molecular processes and that disease results from reorganization of global genome architecture, thereby enabling pathologic gene expression. To test this hypothesis, we will perform the first ever reconstruction of genome topology on distinct cell types—fibroblasts and myocytes—from the same organ. We will precisely measure differences in chromatin architecture in fibroblast nuclei from male and female mice, examining the role of sex differences in genome organization as a potential unexplored contributor to differences in gene expression and cardiovascular phenotype between the sexes. We will use dCas CLOuD9- based chromatin loop reorganization tools to definitively test the causative role of chromatin interactions in transcription and fibroblast activation. Based on preliminary data implicating a privileged role for linker histone H1.0 in cardiac fibroblasts, we will examine the molecular mechanisms whereby H1.0 controls fibroblast gene expression and locus specific chromatin accessibility. We will use gain- and loss-of-function approaches in isolated fibroblasts to examine the role of histone H1.0 to regulate nuclear condensation, fibroblast gel contraction, proliferation and myofibroblast protein expression. We will conclusively determine the in vivo role of histone H1.0 in cardiac fibroblast phenotype under basal conditions and in the setting of pressure overload, beta adrenergic stress by isoproterenol, or ischemic injury. This approach will allow us to test the role of histone H1.0 to regulate assembly of specific chromatin neighborhoods identified in our genome structure studies as well as to examine whether these neighborhoods are reorganized in a histone H1.0-dependent manner in vivo concomitant with development of disease. The proposed experiments will provide mechanistic insights into how histone H1.0 contributes to fibroblast activation and cardiac function in vivo, revealing molecular details underpinning epigenetic control of the heart’s response to injury.


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: 2025 ( Subtotal = $390,000 )
2025	2025	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cardiovascular Diseases Research	000	13	5/16/2025	NON-COMPETING CONTINUATION	$390,000
														Subtotal = $390,000

Issue Date FY: 2024 ( Subtotal = $390,000 )
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cardiovascular Diseases Research	000	12	6/15/2024	NON-COMPETING CONTINUATION	$390,000
														Subtotal = $390,000

Issue Date FY: 2023 ( Subtotal = $390,000 )
2023	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cardiovascular Diseases Research	000	11	6/30/2023	NON-COMPETING CONTINUATION	$390,000
														Subtotal = $390,000

Issue Date FY: 2022 ( Subtotal = $389,814 )
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cardiovascular Diseases Research	001	10	6/13/2022	COMPETING CONTINUATION	$390,000
2022	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cardiovascular Diseases Research	000	9	11/19/2021	NON-COMPETING CONTINUATION	-$186
														Subtotal = $389,814

Issue Date FY: 2020 ( Subtotal = $390,000 )
2020	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cardiovascular Diseases Research	000	9	5/21/2020	NON-COMPETING CONTINUATION	$390,000
														Subtotal = $390,000

Issue Date FY: 2019 ( Subtotal = $390,000 )
2019	2019	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cardiovascular Diseases Research	000	8	5/1/2019	NON-COMPETING CONTINUATION	$390,000
														Subtotal = $390,000

Issue Date FY: 2018 ( Subtotal = $389,792 )
2018	2018	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cardiovascular Diseases Research	000	7	5/14/2018	NON-COMPETING CONTINUATION	$389,792
														Subtotal = $389,792

Issue Date FY: 2017 ( Subtotal = $387,261 )
2017	2017	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cardiovascular Diseases Research	001	6	5/29/2017	COMPETING CONTINUATION	$385,000
2017	2017	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cardiovascular Diseases Research	002	6	6/5/2017	COMPETING CONTINUATION	$2,292
2017	2015	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cardiovascular Diseases Research	000	5	4/3/2017	NON-COMPETING CONTINUATION	-$31
														Subtotal = $387,261

Issue Date FY: 2015 ( Subtotal = $379,225 )
2015	2015	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cardiovascular Diseases Research	001	5	2/20/2015	NON-COMPETING CONTINUATION	$32,725
2015	2015	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cardiovascular Diseases Research	000	5	12/11/2014	NON-COMPETING CONTINUATION	$346,500
														Subtotal = $379,225

Issue Date FY: 2014 ( Subtotal = $377,300 )
2014	2014	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cardiovascular Diseases Research	000	4	1/10/2014	NON-COMPETING CONTINUATION	$346,500
2014	2014	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cardiovascular Diseases Research	001	4	6/3/2014	NON-COMPETING CONTINUATION	$30,800
														Subtotal = $377,300

Issue Date FY: 2013 ( Subtotal = $366,520 )
2013	2013	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cardiovascular Diseases Research	001	3	7/3/2013	NON-COMPETING CONTINUATION	$20,020
2013	2013	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cardiovascular Diseases Research	000	3	1/7/2013	NON-COMPETING CONTINUATION	$346,500
														Subtotal = $366,520

Issue Date FY: 2012 ( Subtotal = $385,000 )
2012	2012	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cardiovascular Diseases Research	000	2	1/6/2012	NON-COMPETING CONTINUATION	$346,500
2012	2012	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cardiovascular Diseases Research	001	2	5/10/2012	NON-COMPETING CONTINUATION	$38,500
														Subtotal = $385,000

Issue Date FY: 2011 ( Subtotal = $385,000 )
2011	2011	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cardiovascular Diseases Research	000	1	12/20/2010	NEW	$385,000
														Subtotal = $385,000

Grand Total All Awards = $5,009,912

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Dynamics of cardiac nuclei in heart disease

Award Number: R01HL105699

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2011

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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