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Regulation of cardiac pacemaker cell cytoarchitecture

Award Number: R01HL146626
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/05/2019
PERIOD OF PERFORMANCE END DATE: 02/28/2029

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Regulation of cardiac pacemaker cell cytoarchitecture - ABSTRACT: Cardiac pacemaker cells (CPCs) rhythmically initiate the electrical impulses that stimulate heart contraction. CPC dysfunction co-segregates with a broad variety of both cardiac and non-cardiac disease conditions and represents the leading cause for the surgical implantation of artificial pacemakers. Moreover, CPC dysfunction is a leading cause of sudden death among heart failure patients. Despite clinical burden of CPC dysfunction, very little is currently known regarding the cellular pathologies that disrupt normal pacemaking. Indeed, we lack even a basic understanding of the cellular and environmental conditions required for CPC homeostasis. Over the previous funding period, work conducted within this R01 has uncovered a novel paradigm demonstrating that CPCs require low cellular strain to maintain the cytoarchitectural features necessary for their function. Thus, the focus of this renewal application is to define the molecular pathways that produce a microenvironmental niche around CPCs that functionally minimizes cellular strain. Importantly, our preliminary data now demonstrate that CPCs express unique classes of paracrine factors which specifically activate their local interstitial support cells. This activation drives the formation of a biomechanically compliant extracellular matrix that surrounds and encapsulates CPCs (protecting them from contractile and hemodynamic forces present throughout the rest of the heart). We have also identified that ectopically increasing cellular strain results in breakdown of CPC activity and the loss of paracrine activation of their local interstitial cells. Collectively, these data have led to the hypothesis that a mechano-paracrine positive feedback loop co-regulates the behavior of CPCs and their support cells patterning the local tissue mechanics required for CPC activity. We will test this by defining the specific molecular pathways that integrate mechanical feedback within CPC (Aim1), identifying the paracrine factors that maintain CPC-interstitial cell crosstalk (Aim2), and determining how CPC-interstitial interactions changes under conditions of aging or pathological cardiac remodeling (Aim3). Thus, successful execution of this proposal will create a novel and holistic model of CPC homeostasis that accounts for the cooperative activity of multiple cell types within the sinoatrial node. We project these studies will establish fundamental principles that define CPC developmental optimization, inform our overall understanding of CPC- related disease progression, and instruct tissue engineering approaches designed to generate biological pacing systems for therapeutic purposes.


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 = $601,676 )
2025	2025	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cardiovascular Diseases Research	002	7	3/25/2025	NON-COMPETING CONTINUATION	$541,509
2025	2025	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cardiovascular Diseases Research	003	7	8/4/2025	NON-COMPETING CONTINUATION	$60,167
2025	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cardiovascular Diseases Research	001	6	3/18/2025	COMPETING CONTINUATION	$10,780
2025	2023	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cardiovascular Diseases Research	000	5	3/18/2025	NON-COMPETING CONTINUATION	-$10,780
														Subtotal = $601,676

Issue Date FY: 2024 ( Subtotal = $604,786 )
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cardiovascular Diseases Research	001	6	6/21/2024	COMPETING CONTINUATION	$60,478
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cardiovascular Diseases Research	000	6	12/20/2023	COMPETING CONTINUATION	$544,308
														Subtotal = $604,786

Issue Date FY: 2023 ( Subtotal = $312,116 )
2023	2023	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cardiovascular Diseases Research	000	5	2/10/2023	NON-COMPETING CONTINUATION	$388,750
2023	2022	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cardiovascular Diseases Research	001	4	8/17/2023	SUPPLEMENT FOR EXPANSION	-$76,634
														Subtotal = $312,116

Issue Date FY: 2022 ( Subtotal = $465,384 )
2022	2022	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cardiovascular Diseases Research	000	4	5/26/2022	NON-COMPETING CONTINUATION	$388,750
2022	2022	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cardiovascular Diseases Research	001	4	5/27/2022	SUPPLEMENT FOR EXPANSION	$76,634
														Subtotal = $465,384

Issue Date FY: 2021 ( Subtotal = $465,384 )
2021	2021	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cardiovascular Diseases Research	000	3	3/23/2021	NON-COMPETING CONTINUATION	$465,384
														Subtotal = $465,384

Issue Date FY: 2020 ( Subtotal = $427,068 )
2020	2020	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cardiovascular Diseases Research	001	2	9/15/2020	SUPPLEMENT FOR EXPANSION	$38,318
2020	2020	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cardiovascular Diseases Research	000	2	2/14/2020	NON-COMPETING CONTINUATION	$388,750
														Subtotal = $427,068

Issue Date FY: 2019 ( Subtotal = $388,750 )
2019	2019	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cardiovascular Diseases Research	000	1	4/2/2019	NEW	$388,750
														Subtotal = $388,750

Grand Total All Awards = $3,265,164

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Regulation of cardiac pacemaker cell cytoarchitecture

Award Number: R01HL146626

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/05/2019

PERIOD OF PERFORMANCE END DATE: 02/28/2029

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