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Interrogating stress-relieving neural circuits to alleviate cardiovascular disease

Award Number: R35HL150750
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/05/2020
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Interrogating stress-relieving neural circuits to alleviate cardiovascular disease - Project Summary Stressful life events are linked to the etiology of cardiovascular disease (CVD), which is the leading cause of death in the U.S. The mechanisms by which stress causes pathophysiology contributing to CVD are poorly understood and effective therapeutics that relieve stress and improve cardiovascular health are lacking. A premise of this proposal is that exploration of the neural circuits controlling the perception of stress may provide insight towards mechanisms underlying CVD and interventions aimed at its reversal. Causally-linking patterns of neural activity to stress and the development of CVD in humans is challenging. However, preclinical studies using laboratory mice that implement modern neuroscience and genetic technologies to excite or inhibit specific neural circuits make causally-linking neural activity and indices of stress responsiveness achievable. Using genetically-modified mice, we revealed that the activity of neurons that express genes encoding particular angiotensin receptor subtypes is coupled to cardiovascular, neuroendocrine and behavioral responses to stress. Specifically, we discovered that neurons expressing the angiotensin type-2 (AT2R) and Mas receptor (MasR) densely populate cortical and limbic brain regions controlling the perception of psychological stress and that excitation of these neurons decreases blood pressure, heart rate, circulating levels of corticosterone and anxiety- like behavior. In the periphery, we discovered that the nodose ganglion is densely populated by neurons expressing the angiotensin type 1a receptor (AT1R). These neurons function as primary baroreceptor afferents and excitation of these neurons lowers blood pressure, heart rate and energy expenditure. Collectively, these observations have led to the overall hypothesis that excitation of particular neuronal populations that express the AT1R, AT2R or MasR alters the perception of stress to protect against CVD. Experiments will use the Cre-LoxP system in mice with a cadre of modern neuroscience techniques and classical systems physiology to confirm or refute this hypothesis. Initial experiments utilize Cre-diver mice with virally-mediated gene transfer and in vivo optogenetics to determine whether the excitation or inhibition of neurons that express AT1R, AT2R, or MasR attenuates or exacerbates stress responding. Subsequent experiments use a model of stress-induced pathophysiology to evaluate how the structure and function of neurons that express the AT1R, AT2R or MasR is altered by disease. The final experiments attempt to alleviate stress-induced pathophysiology with optogenetic, genetic or pharmacological manipulations that alter the excitability of neurons that express the AT1R, AT2R or MasR. We anticipate that the proposed research will reveal, at a detailed and mechanistic level, neural circuits that provide stress relief, thereby guiding development of novel therapeutics for CVD.


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 = $842,400 )
2025	2025	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION INC	58 EDGEWOOD AVE NE	ATLANTA	GA	30303	FULTON	USA	Cardiovascular Diseases Research	000	6	11/22/2024	NON-COMPETING CONTINUATION	$842,400
2025	2024	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION INC	58 EDGEWOOD AVE NE	ATLANTA	GA	30303	FULTON	USA	Cardiovascular Diseases Research	002	5	2/25/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$583,300
2025	2023	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cardiovascular Diseases Research	001	4	2/25/2025	NON-COMPETING CONTINUATION	-$583,300
														Subtotal = $842,400

Issue Date FY: 2024 ( Subtotal = $917,282 )
2024	2024	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION INC	58 EDGEWOOD AVE NE	ATLANTA	GA	30303	FULTON	USA	Cardiovascular Diseases Research	002	5	12/5/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$49,362
2024	2024	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION INC	58 EDGEWOOD AVE NE	ATLANTA	GA	30303	FULTON	USA	Cardiovascular Diseases Research	003	5	5/8/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$74,882
2024	2024	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION INC	58 EDGEWOOD AVE NE	ATLANTA	GA	30303	FULTON	USA	Cardiovascular Diseases Research	001	5	11/24/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$793,038
2024	2023	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cardiovascular Diseases Research	000	4	11/22/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $917,282

Issue Date FY: 2023 ( Subtotal = $861,384 )
2023	2023	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cardiovascular Diseases Research	000	4	1/17/2023	NON-COMPETING CONTINUATION	$775,247
2023	2023	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cardiovascular Diseases Research	001	4	3/3/2023	NON-COMPETING CONTINUATION	$86,137
														Subtotal = $861,384

Issue Date FY: 2022 ( Subtotal = $861,384 )
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cardiovascular Diseases Research	001	3	1/13/2022	NON-COMPETING CONTINUATION	$775,246
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cardiovascular Diseases Research	002	3	6/13/2022	NON-COMPETING CONTINUATION	$86,138
2022	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cardiovascular Diseases Research	000	2	1/7/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $861,384

Issue Date FY: 2021 ( Subtotal = $719,807 )
2021	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cardiovascular Diseases Research	000	2	1/20/2021	NON-COMPETING CONTINUATION	$647,826
2021	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cardiovascular Diseases Research	001	2	5/25/2021	NON-COMPETING CONTINUATION	$71,981
														Subtotal = $719,807

Issue Date FY: 2020 ( Subtotal = $733,362 )
2020	2020	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cardiovascular Diseases Research	000	1	2/4/2020	NEW	$733,362
														Subtotal = $733,362

Grand Total All Awards = $4,935,619

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Interrogating stress-relieving neural circuits to alleviate cardiovascular disease

Award Number: R35HL150750

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/05/2020

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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