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Interrogating distinct angiotensin type-1 and type-2 receptor containing brain circuits to understand and alleviate hypertension

Award Number: R01HL145028
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary Hypertension is a widespread health problem and a major risk factor for cardiovascular disease. Nearly one- third of hypertensive patients suffer from drug-resistant hypertension; a condition associated with activation of brain angiotensin receptors, enhanced sympathetic nervous system activity and elevated levels of circulating vasopressin. The proposed experiments aim to identify neurons within the brain whose excitation or inhibition is coupled to the pathophysiology underlying resistant hypertension. Our preliminary studies using mice with Cre recombinase or green fluorescent protein directed by the genes for the angiotensin type 1a or type 2 receptors (AT1R or AT2R) have provided intriguing insight. We have discovered that neurons in the organum vasculosum of the lamina terminalis (OVLT) and median preoptic nucleus (MnPO) express AT1R or AT2R and send dense excitatory projections to the paraventricular nucleus of the hypothalamus (PVN) and peri-PVN area, respectively. Fascinatingly, optogenetic excitation of such AT1R neurons elicits robust (>40 mmHg) and sustained increases in blood pressure, suggestive of sympathoexcitation and augmented vasopressin secretion. Within the MnPO/OVLT the vast majority of AT2R(s) are NOT expressed on neurons that also synthesize AT1R, but rather, are a separate population of neurons whose excitation may oppose the onset of hypertension. Consistent with this interpretation, we recently discovered that pharmacological activation of AT2R facilitates GABAergic mediated inhibition of vasopressin neurons and reduces systemic vasopressin and blood pressure. We have developed the overall hypothesis that neurons within the MnPO/OVLT that express AT1R or AT2R project to the PVN and peri-PVN area to coordinate sympathetic outflow and vasopressin secretion, and that the relative activities of these neurons predict resistance or susceptibility to hypertension. To address this hypothesis, the proposed studies combine Cre-LoxP technology, in vitro/in vivo optogenetics and classical systems physiology with a mouse model of hypertension. Aim 1 will use optogenetics to probe the connection between neurons in the MnPO/OVLT that express AT1R or AT2R and neurons in the PVN that express vasopressin. Sufficiency and/or necessity of these connections will be determined for the increased sympathetic nervous system activity and vasopressin secretion that promote neurogenic hypertension. Then, Aim 2 will use the Cre-loxP system to delete AT1R and/or AT2R within the MnPO/OVLT and determine whether AT1R/AT2R signaling within these brain nuclei contribute to the etiology of hypertension. Collectively, these experiments will determine whether excitability and/or AT1R/AT2R signaling within this neural circuit can be altered to prevent high blood pressure. These studies have the potential to uncover, at a detailed and mechanistic level, the neural circuits that are compromised during hypertension and, in the long-term, may inform a therapeutic strategy that optimally targets excitation of AT1R- and AT2R-containing neurons to relieve hypertension.


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	2023	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cardiovascular Diseases Research	000	5	11/23/2023	NON-COMPETING CONTINUATION	-$225,597
2024	2023	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION INC	58 EDGEWOOD AVE NE	ATLANTA	GA	30303	FULTON	USA	Cardiovascular Diseases Research	001	6	11/24/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$225,597
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $375,597 )
2023	2023	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cardiovascular Diseases Research	000	5	11/11/2022	NON-COMPETING CONTINUATION	$338,037
2023	2023	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cardiovascular Diseases Research	001	5	2/11/2023	NON-COMPETING CONTINUATION	$37,560
														Subtotal = $375,597

Issue Date FY: 2022 ( Subtotal = $375,597 )
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cardiovascular Diseases Research	001	4	6/8/2022	NON-COMPETING CONTINUATION	$37,560
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cardiovascular Diseases Research	000	4	11/5/2021	NON-COMPETING CONTINUATION	$338,037
														Subtotal = $375,597

Issue Date FY: 2021 ( Subtotal = $375,597 )
2021	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cardiovascular Diseases Research	000	3	11/30/2020	NON-COMPETING CONTINUATION	$338,037
2021	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cardiovascular Diseases Research	001	3	5/24/2021	NON-COMPETING CONTINUATION	$37,560
														Subtotal = $375,597

Issue Date FY: 2020 ( Subtotal = $375,597 )
2020	2020	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cardiovascular Diseases Research	001	2	1/23/2020	NON-COMPETING CONTINUATION	$18,780
2020	2020	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cardiovascular Diseases Research	000	2	11/27/2019	NON-COMPETING CONTINUATION	$356,817
														Subtotal = $375,597

Issue Date FY: 2019 ( Subtotal = $375,597 )
2019	2019	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cardiovascular Diseases Research	000	1	1/10/2019	NEW	$375,597
														Subtotal = $375,597

Grand Total All Awards = $1,877,985

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Interrogating distinct angiotensin type-1 and type-2 receptor containing brain circuits to understand and alleviate hypertension

Award Number: R01HL145028

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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