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Forebrain electroneutral transporters in salt-sensitive hypertension

Award Number: R01HL163906
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/08/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Forebrain electroneutral transporters in salt-sensitive hypertension - PROJECT SUMMARY/ABSTRACT Excess dietary salt intake is associated with cardiovascular disease and is a major contributing factor to the pathogenesis of hypertension. Salt-sensitive hypertension in both humans and rodent models is associated with elevations in plasma or cerebrospinal fluid [NaCl]. The resultant relative hypernatremia activates central circuits to increase sympathetic nerve activity (SNA) and arterial blood pressure (ABP). There are brain NaCl-sensors in the circumventricular organs such as the organum vasculosum of the lamina terminalis (OVLT) and subfornical organ (SFO); activation of OVLT/SFO neurons stimulates thirst, vasopressin (AVP) secretion, and SNA, whereas interruption of neurotransmission in OVLT/SFO lowers ABP in salt-sensitive models. However, the mechanisms by which OVLT/SFO neurons sense extracellular [NaCl] are not known. Recent data suggest the Na+-K+-2Cl- co-transporter (NKCC2) is not kidney specific but is also expressed in brain regions that regulate whole body NaCl and water homeostasis. The central hypothesis of this proposal is that the ingestion of excess dietary salt elevates extracellular [NaCl] to activate NaCl-sensitive neurons in the OVLT/SFO through NKCC2. In turn, this activates descending pathways to elevate SNA and ABP. Furthermore, we hypothesize that these NaCl-sensing mechanisms are sensitized in salt-sensitive humans, since our preliminary data show hypernatremia evokes a greater increase in OVLT discharge of Dahl-salt sensitive versus Dahl-salt resistant rats fed a high salt diet. We propose 2 specific aims. Specific Aim 1 will determine the extent by which NKCC2 mediates NaCl-sensing in OVLT/SFO neurons and elevate SNA and ABP to acute NaCl loading or chronic salt- sensitive hypertension in rodents. Specific Aim 2 will test the hypothesis that an NKCC2 antagonist will blunt hypernatremia-induced central neural activation and SNA in salt resistant and salt sensitive adults with high BP, and that central neural activation will be greater in salt sensitive adults, suggesting heightened sodium sensing. Successful completion of these aims will provide needed information on the cellular elements that mediate intrinsic NaCl-sensing of hypothalamic neurons and provide novel data on central sodium sensing in salt sensitive humans. This is a translational R01, bringing two laboratories together that have a track record of successful collaboration, and these studies will provide a framework for the development of novel therapeutic treatments of salt-sensitive 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: 2025 ( Subtotal = $627,861 )
2025	2025	UNIVERSITY OF DELAWARE	550 S COLLEGE AVE	NEWARK	DE	19713	NEW CASTLE	USA	Cardiovascular Diseases Research	001	3	5/1/2025	NON-COMPETING CONTINUATION	$627,861
2025	2024	UNIVERSITY OF DELAWARE	550 S COLLEGE AVE	NEWARK	DE	19713	NEW CASTLE	USA	Cardiovascular Diseases Research	000	2	1/14/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $627,861

Issue Date FY: 2024 ( Subtotal = $695,521 )
2024	2024	UNIVERSITY OF DELAWARE	220 HULLIHEN HALL	NEWARK	DE	19716	NEW CASTLE	USA	Cardiovascular Diseases Research	000	2	5/30/2024	NON-COMPETING CONTINUATION	$695,521
														Subtotal = $695,521

Issue Date FY: 2023 ( Subtotal = $720,426 )
2023	2023	UNIVERSITY OF DELAWARE	220 HULLIHEN HALL	NEWARK	DE	19716	NEW CASTLE	USA	Cardiovascular Diseases Research	001	1	7/19/2023	NEW	$0
2023	2023	UNIVERSITY OF DELAWARE	220 HULLIHEN HALL	NEWARK	DE	19716	NEW CASTLE	USA	Cardiovascular Diseases Research	000	1	6/8/2023	NEW	$720,426
														Subtotal = $720,426

Grand Total All Awards = $2,043,808

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Forebrain electroneutral transporters in salt-sensitive hypertension

Award Number: R01HL163906

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/08/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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