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Role of RhoA in the Molecular Pathogenesis of Heart Disease.

Award Number: R01HL102368
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/15/2010
PERIOD OF PERFORMANCE END DATE: 12/31/2022

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Role of RhoA in the Molecular Pathogenesis of Heart Disease. - 7. Project Summary/Abstract Heart failure is a progressive disease characterized by cardiomyocyte (CM) loss, interstitial fibrosis, loss of ventricular compliance and chamber remodeling. CMs change in response to pathological stimuli, altering their cell morphology, increasing protein synthesis and upregulating fetal genes. Though initially compensatory, these changes eventually become maladaptive, inducing fibrosis and adverse cardiac responses. Cardiac fibroblasts (FBs) are implicated in regulating aspects of this deleterious profile, but specific molecular mechanisms regulating their function remain unclear. FBs are, however, known to be significant effectors of cardiac function, where they act as principal determinants of ventricular remodeling and fibrosis in response to stress and injury. In chronic disease states, however, this fibrotic response leads to reduced wall compliance, decreased diffusion efficiency, and arrhythmias. Thus, limiting fibrosis and the activity of myofibroblasts under conditions of chronic stress would be beneficial in preventing heart failure. As part of our original grant, we generated mice with CM- specific deletion of RhoA, a Ras-related small G protein, to determine the molecular mechanisms of its activity specifically in myocardium. In response to chronic stress, we found that hearts from these mice developed accelerated dilation, with significant loss of contractile function. However, and despite the heart failure pathology, they also had significantly reduced cardiac fibrosis, with a demonstrated decrease in transcriptional activation of genes involved in the fibrotic response, including the serum response factor (SRF) and myocardin related transcription factors (MRTF). Together, our data suggest that RhoA is a critical and nodal enzyme in cardiac injury, functioning to both preserve contractility and to mediate activation of profibrotic genes. Here, in this renewal application, we propose to specifically interrogate the functional and mechanistic role(s) for RhoA signaling in fibrosis. We hypothesize that RhoA modulates FB activity both directly, within the activated FB, as well as indirectly, through CM-specific paracrine signals, to mediate myofibroblast activation and/or response to cardiac stress and injury. We propose to 1) examine the CM-specific RhoA-mediated paracrine signals that drive myofibroblast transformation and activation; 2) determine if RhoA signaling is necessary and sufficient for myofibroblast propagation in activated FBs; 3) utilize novel nanoparticle targeted technology to deliver cell specific inhibitors of RhoA effectors to ameliorate fibrosis and to prevent cardiac disease progression. These data will verify, for the first time, the primacy of the RhoA pathway in the fibrotic response in vivo and will identify novel targets and therapeutic strategies for the treatment of cardiac fibrosis and heart failure.


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 = $0 )
2024	2021	MASONIC MEDICAL RESEARCH LAB	2150 BLEECKER ST	UTICA	NY	13501	ONEIDA	USA	Cardiovascular Diseases Research	000	9	10/19/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $753,797 )
2021	2021	MASONIC MEDICAL RESEARCH LABORATORY	2150 BLEECKER ST	UTICA	NY	13501	ONEIDA	USA	Cardiovascular Diseases Research	002	9	5/18/2021	NON-COMPETING CONTINUATION	$75,379
2021	2021	MASONIC MEDICAL RESEARCH LABORATORY	2150 BLEECKER ST	UTICA	NY	13501	ONEIDA	USA	Cardiovascular Diseases Research	001	9	12/30/2020	NON-COMPETING CONTINUATION	$678,418
2021	2020	MASONIC MEDICAL RESEARCH LABORATORY	2150 BLEECKER ST	UTICA	NY	13501	ONEIDA	USA	Cardiovascular Diseases Research	000	8	10/26/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $753,797

Issue Date FY: 2020 ( Subtotal = $797,343 )
2020	2020	MASONIC MEDICAL RESEARCH LABORATORY	2150 BLEECKER ST	UTICA	NY	13501	ONEIDA	USA	Cardiovascular Diseases Research	001	8	1/28/2020	NON-COMPETING CONTINUATION	$39,868
2020	2020	MASONIC MEDICAL RESEARCH LABORATORY	2150 BLEECKER ST	UTICA	NY	13501	ONEIDA	USA	Cardiovascular Diseases Research	000	8	12/12/2019	NON-COMPETING CONTINUATION	$757,475
														Subtotal = $797,343

Issue Date FY: 2019 ( Subtotal = $763,525 )
2019	2019	MASONIC MEDICAL RESEARCH LABORATORY	2150 BLEECKER ST	UTICA	NY	13501	ONEIDA	USA	Cardiovascular Diseases Research	003	7	2/13/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$499,090
2019	2019	MASONIC MEDICAL RESEARCH LABORATORY	2150 BLEECKER ST	UTICA	NY	13501	ONEIDA	USA	Cardiovascular Diseases Research	001	7	1/11/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$763,525
2019	2018	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cardiovascular Diseases Research	002	6	2/13/2019	COMPETING CONTINUATION	-$499,090
2019	2018	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cardiovascular Diseases Research	000	6	1/11/2019	COMPETING CONTINUATION	$0
														Subtotal = $763,525

Issue Date FY: 2018 ( Subtotal = $704,922 )
2018	2018	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cardiovascular Diseases Research	000	6	1/5/2018	COMPETING CONTINUATION	$704,922
														Subtotal = $704,922

Issue Date FY: 2014 ( Subtotal = $422,037 )
2014	2014	BETH ISRAEL HOSPITAL	330 BROOKLINE AVENUE	BOSTON	MA	02215	SUFFOLK	USA	Cardiovascular Diseases Research	000	5	3/11/2014	NON-COMPETING CONTINUATION	$422,037
														Subtotal = $422,037

Issue Date FY: 2013 ( Subtotal = $409,979 )
2013	2013	BETH ISRAEL HOSPITAL	330 BROOKLINE AVENUE	BOSTON	MA	02215	SUFFOLK	USA	Cardiovascular Diseases Research	001	4	7/5/2013	NON-COMPETING CONTINUATION	$22,394
2013	2013	BETH ISRAEL HOSPITAL	330 BROOKLINE AVENUE	BOSTON	MA	02215	SUFFOLK	USA	Cardiovascular Diseases Research	000	4	4/6/2013	NON-COMPETING CONTINUATION	$387,585
														Subtotal = $409,979

Issue Date FY: 2012 ( Subtotal = $430,650 )
2012	2012	BETH ISRAEL HOSPITAL	330 BROOKLINE AVENUE	BOSTON	MA	02215	SUFFOLK	USA	Cardiovascular Diseases Research	000	3	3/6/2012	NON-COMPETING CONTINUATION	$430,650
														Subtotal = $430,650

Issue Date FY: 2011 ( Subtotal = $435,000 )
2011	2011	BETH ISRAEL HOSPITAL	330 BROOKLINE AVENUE	BOSTON	MA	02215	SUFFOLK	USA	Cardiovascular Diseases Research	000	2	3/3/2011	NON-COMPETING CONTINUATION	$435,000
														Subtotal = $435,000

Issue Date FY: 2010 ( Subtotal = $430,821 )
2010	2010	BETH ISRAEL HOSPITAL	330 BROOKLINE AVENUE	BOSTON	MA	02215	SUFFOLK	USA	Cardiovascular Diseases Research	000	1	4/15/2010	NEW	$430,821
														Subtotal = $430,821

Grand Total All Awards = $5,148,074

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Role of RhoA in the Molecular Pathogenesis of Heart Disease.

Award Number: R01HL102368

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/15/2010

PERIOD OF PERFORMANCE END DATE: 12/31/2022

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