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Antihypertensive Mechanisms of Minocycline in Resistant Hypertension: Role of the gut microbiota-brain-immune axis

Award Number: R01HL132448
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Antihypertensive Mechanisms of Minocycline in Resistant Hypertension: Role of the gut microbiota-brain-immune axis - PROJECT SUMMARY Hypertension (HTN) is the most prevalent modifiable risk for cardiovascular disease (CVD) and disorders directly influencing CVD (i.e., diabetes, chronic kidney disease, obstructive sleep apnea, etc.). Despite lifestyle changes and drug therapy advances, ~20-30% of patients with treated HTN are “resistant” to (require ≥3) antihypertensive drugs. TRH is generally thought to originate through volume overload and autonomic nervous system (ANS) dysfunction that impairs immune function and inflammatory response. However, few treatment options are available for patients with TRH and promising procedures (e.g., renal artery sympathetic denervation) remain inaccessible to most. Thus, a mechanism-based breakthrough is imperative to foster development of novel medical-based strategies to better control blood pressure (BP) and potentially cure and/or prevent TRH. Our prior funding period provides strong evidence for an altered gut microbiota-gut leakiness- neuroinflammation interaction hypothesis in which gut dysbiosis and gut leakiness, combined with neuroinflammation, perpetuate neurogenic HTN and contribute to TRH and possibly to racial disparities in TRH. We also showed that minocycline, an antibiotic with anti-inflammatory properties, appears to reduce BP in animal HTN models as well as among patients with TRH. In this renewal application, we propose to elucidate mechanisms that underlie the effects of minocycline on BP-lowering in White and African American individuals with TRH. Our overarching objective is to test the hypothesis that minocycline rebalances gut dysbiosis, namely by increasing butyrate-producing functional capacity, attenuating gut-mediated inflammatory response and gut leakiness, and that these effects explain BP-lowering effects in TRH. Four specific aims are proposed to support/refute this altered gut microbiota-gut leakiness- neuroinflammation interaction hypothesis in TRH: Aim 1 will investigate the hypothesis that minocycline alters gut microbiota (primarily butyrate-producing capacity) that mediates minocycline-induced BP lowering in TRH. Aim 2 will assess the extent to which minocycline alters gut-associated inflammation and gut leakiness, and their response with BP changes after minocycline treatment. Aim 3 will evaluate the hypothesis that minocycline reduces neuroinflammation in TRH. Aim 4 will evaluate the hypothesis that these effects of minocycline differ in White versus African American individuals. Together, these studies will elucidate ANS-based mechanisms of host-microbiota interactions in TRH, evaluate potential of minocycline to reduce TRH, and serve as proof of concept for other therapeutic options that rebalance microbiota or mitigate TRH-associated inflammation, to improve BP control in patients with TRH, who remain at high risk.


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 = $585,021 )
2025	2025	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cardiovascular Diseases Research	000	6	2/26/2025	NON-COMPETING CONTINUATION	$585,021
														Subtotal = $585,021

Issue Date FY: 2024 ( Subtotal = $682,943 )
2024	2024	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cardiovascular Diseases Research	000	5	2/20/2024	COMPETING CONTINUATION	$682,943
														Subtotal = $682,943

Issue Date FY: 2023 ( Subtotal = -$8 )
2023	2019	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cardiovascular Diseases Research	000	4	11/21/2022	NON-COMPETING CONTINUATION	-$8
														Subtotal = -$8

Issue Date FY: 2022 ( Subtotal = -$3,686 )
2022	2019	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cardiovascular Diseases Research	000	4	4/19/2022	NON-COMPETING CONTINUATION	-$3,686
														Subtotal = -$3,686

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2019	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cardiovascular Diseases Research	000	4	3/30/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $617,909 )
2019	2019	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cardiovascular Diseases Research	000	4	3/22/2019	NON-COMPETING CONTINUATION	$617,909
														Subtotal = $617,909

Issue Date FY: 2018 ( Subtotal = $640,271 )
2018	2018	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cardiovascular Diseases Research	000	3	3/22/2018	NON-COMPETING CONTINUATION	$627,465
2018	2018	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cardiovascular Diseases Research	001	3	7/2/2018	NON-COMPETING CONTINUATION	$12,806
														Subtotal = $640,271

Issue Date FY: 2017 ( Subtotal = $665,271 )
2017	2017	UNIVERSITY OF FLORIDA	207 GRINTER HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Cardiovascular Diseases Research	000	2	3/31/2017	NON-COMPETING CONTINUATION	$665,271
														Subtotal = $665,271

Issue Date FY: 2016 ( Subtotal = $617,909 )
2016	2016	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Cardiovascular Diseases Research	000	1	3/26/2016	NEW	$617,909
														Subtotal = $617,909

Grand Total All Awards = $3,805,630

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Antihypertensive Mechanisms of Minocycline in Resistant Hypertension: Role of the gut microbiota-brain-immune axis

Award Number: R01HL132448

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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