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MOLECULAR AND CELLULAR CONTROL OF ANGIOGENESIS

Award Number: R35HL139950
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2018
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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MOLECULAR AND CELLULAR CONTROL OF ANGIOGENESIS - ABSTRACT Endothelial cells (EC) mount distinct cellular responses to signaling inputs as primitive vessel networks expand via sprouting angiogenesis. This heterogeneity in cellular behaviors is achieved by differential signaling of key pathways such as VEGF-A and BMP. Underlying differences in signaling is EC heterogeneity at the level of gene expression and post-translational protein regulation. We define EC heterogeneity as distinct cellular behaviors in response to either molecular or mechanical signals, accompanied by variation in expression profiles and regulation of key pathway regulators. My lab has contributed to understanding how VEGF-A and BMP signaling contribute to EC heterogeneity and how Notch co-ordinates these pathways. Heterogeneity is lost as vessels respond to flow- mediated signals and remodel, and vessels “reactivate” to sprout and form new networks during physiological wound healing. These observations lead to several questions whose answers will impact our basic understanding of blood vessel formation and function, and help understand cardiovascular diseases. Our goals going forward are to investigate developmental EC heterogeneity, to examine how heterogeneity is lost as vessels remodel to homeostasis, and to test the novel hypothesis that reactivation of developmental EC heterogeneity contributes to wound healing angiogenesis. We will use both models and tools that we've developed and successfully used to date, and also incorporate new state-of-the-art approaches and tools to extend the impact of our findings beyond early sprouting angiogenesis. Our over-arching hypothesis is that EC heterogeneity is promoted by low or absent flow-induced shear stress, and repressed when shear stress reaches a critical threshold(s) by transitions in regulation of signaling pathways. We further posit that wound healing angiogenesis is promoted by reduced shear stress downstream inflammation-induced tortuous vessel formation. We will focus on the respective roles of VEGF- A and BMP signaling in these processes. This new knowledge will fill critical gaps in our knowledge of how EC achieve this remarkable transition from heterogeneous outputs to homeostasis to reactivation. This new knowledge, in turn, will allow us and others to examine more precisely how dysregulation of EC transitions contributes to disease.


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 = $0 )
2025	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cardiovascular Diseases Research	000	7	12/16/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $903,848 )
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cardiovascular Diseases Research	001	7	6/24/2024	NON-COMPETING CONTINUATION	$73,783
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cardiovascular Diseases Research	000	7	12/26/2023	NON-COMPETING CONTINUATION	$830,065
														Subtotal = $903,848

Issue Date FY: 2023 ( Subtotal = $922,295 )
2023	2023	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cardiovascular Diseases Research	002	6	3/3/2023	NON-COMPETING CONTINUATION	$92,230
2023	2023	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cardiovascular Diseases Research	001	6	11/21/2022	NON-COMPETING CONTINUATION	$830,065
2023	2022	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cardiovascular Diseases Research	000	5	10/21/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $922,295

Issue Date FY: 2022 ( Subtotal = $922,295 )
2022	2022	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cardiovascular Diseases Research	000	5	12/8/2021	NON-COMPETING CONTINUATION	$830,065
2022	2022	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cardiovascular Diseases Research	001	5	6/8/2022	NON-COMPETING CONTINUATION	$92,230
														Subtotal = $922,295

Issue Date FY: 2021 ( Subtotal = $922,295 )
2021	2021	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cardiovascular Diseases Research	001	4	5/15/2021	NON-COMPETING CONTINUATION	$92,230
2021	2021	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cardiovascular Diseases Research	000	4	1/27/2021	NON-COMPETING CONTINUATION	$830,065
														Subtotal = $922,295

Issue Date FY: 2020 ( Subtotal = $922,295 )
2020	2020	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cardiovascular Diseases Research	000	3	12/25/2019	NON-COMPETING CONTINUATION	$876,179
2020	2020	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cardiovascular Diseases Research	001	3	3/13/2020	NON-COMPETING CONTINUATION	$46,116
														Subtotal = $922,295

Issue Date FY: 2019 ( Subtotal = $922,295 )
2019	2019	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cardiovascular Diseases Research	000	2	12/21/2018	NON-COMPETING CONTINUATION	$922,295
														Subtotal = $922,295

Issue Date FY: 2018 ( Subtotal = $922,296 )
2018	2018	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cardiovascular Diseases Research	000	1	12/26/2017	NEW	$922,296
														Subtotal = $922,296

Grand Total All Awards = $6,437,619

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MOLECULAR AND CELLULAR CONTROL OF ANGIOGENESIS

Award Number: R35HL139950

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2018

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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