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Neuroimmune Mechanisms of Kinin B1 Receptor in Hypertension

Award Number: R01HL153115
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2020
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Neuroimmune Mechanisms of Kinin B1 Receptor in Hypertension - Project Summary/Abstract Hypertension (HTN) remains an important medical and public health issue in the United States. Most current therapeutic measures are targeted against the peripheral renin-angiotensin system (RAS). These therapies have reduced the morbidity and mortality in hypertensive patients. However, the long-term prognosis in patients with hypertension remains poor, and new therapeutic approaches are needed. We previously showed that inhibiting brain ADAM17 (A Disintegrin and Metalloprotease) or angiotensin II type 1 receptor (AT1R) upregulation will reduce the progression of HTN. Our recent work indicates that kinin B1 receptor (B1R) activation leads to elevated inflammation in key autonomic brain regions such as the hypothalamic paraventricular nucleus (PVN) and pharmacological blockade or genetic deletion of B1R attenuates neurogenic HTN. In addition, our preliminary data shows that B1R expression is elevated in the PVN of hypertensive human subjects. Evidence suggests that elevated kininase I (carboxypeptidase, CPN/CPM that cleaves bradykinin into des-Arg9- bradykinin, an endogenous agonist for B1R) levels account for increasing endogenous levels of B1R agonists, leading to subsequent upregulation and activation of B1R. Stimulation of B1R results in ADAM17 activation that in turn transactivates epidermal growth factor receptor (EGFR). However, the exact signal transduction mechanisms of B1R and Kininase I, and interactions of AT1R, ADAM17 and EGFR with B1R, in HTN are not clear. Therefore, in this proposal, we test the central hypothesis that the blockade of B1R signaling in the brain reduces inflammation and oxidative stress, thereby decreasing sympathoexcitation, leading to attenuation of neurogenic HTN. This hypothesis will be tested by following specific aims: (1) Determine whether targeted blockade of B1R signaling attenuates neurogenic HTN, (2) Identify the causal role of central B1R activation to the development of neurogenic HTN, and (3) Elucidate the signaling mechanisms and functional interactions between B1R and AT1R/ADAM17/EGFR in the PVN in neurogenic HTN. In terms of approaches, we will use state-of-the-art in vitro and in vivo pharmacological and molecular methods combined with novel and unique genetic models to investigate the signaling mechanisms of B1R in HTN. This project will identify novel and vital role of B1R signaling in HTN and provide insights for developing new therapeutics for the treatment of human neurogenic HTN.


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 = $368,750 )
2024	2024	EAST CAROLINA UNIVERSITY	1000 E 5TH ST	GREENVILLE	NC	27858	PITT	USA	Cardiovascular Diseases Research	000	5	7/19/2024	NON-COMPETING CONTINUATION	$368,750
														Subtotal = $368,750

Issue Date FY: 2023 ( Subtotal = $368,750 )
2023	2023	EAST CAROLINA UNIVERSITY	1000 E 5TH ST	GREENVILLE	NC	27858	PITT	USA	Cardiovascular Diseases Research	000	4	7/28/2023	NON-COMPETING CONTINUATION	$368,750
														Subtotal = $368,750

Issue Date FY: 2022 ( Subtotal = $368,750 )
2022	2022	EAST CAROLINA UNIVERSITY	1000 E 5TH ST	GREENVILLE	NC	27858	PITT	USA	Cardiovascular Diseases Research	000	3	7/20/2022	NON-COMPETING CONTINUATION	$368,750
														Subtotal = $368,750

Issue Date FY: 2021 ( Subtotal = $368,750 )
2021	2021	EAST CAROLINA UNIVERSITY	1000 E 5TH ST	GREENVILLE	NC	27858	PITT	USA	Cardiovascular Diseases Research	000	2	7/17/2021	NON-COMPETING CONTINUATION	$368,750
														Subtotal = $368,750

Issue Date FY: 2020 ( Subtotal = $368,750 )
2020	2020	EAST CAROLINA UNIVERSITY	1000 E 5TH ST	GREENVILLE	NC	27858	PITT	USA	Cardiovascular Diseases Research	000	1	8/13/2020	NEW	$368,750
														Subtotal = $368,750

Grand Total All Awards = $1,843,750

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Neuroimmune Mechanisms of Kinin B1 Receptor in Hypertension

Award Number: R01HL153115

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/15/2020

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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