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Cellular and Molecular Mechanisms of Cardiometabolic Control by Angiotensin in the Brain: Role of AT1 Receptors and Biased Signaling

Award Number: P01HL180287
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2031

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Cellular and Molecular Mechanisms of Cardiometabolic Control by Angiotensin in the Brain: Role of AT1 Receptors and Biased Signaling - Overall Program: Summary The central nervous system plays a major role in blood pressure (BP) and metabolic (MET) regulation but the knowledge of the neural circuits and signal transduction pathways regulating BP, electrolyte balance, and energy expenditure remain incomplete. The central theme of the PPG is to ascertain the convergent and divergent angiotensinergic neural circuits regulating fluid homeostasis, arterial BP, and energy homeostasis, and to clarify the distinctive molecular signaling mechanisms which function to regulate normal homeostasis but are altered in adult hypertension (HT) and obesity or programmed by early-life insults (such as sodium depletion) associated with prematurity. Our hypothesis is dysfunction of basic cellular signaling processes and neural circuits cause sustained alterations in neurohumoral and MET mechanisms; and the renin-angiotensin system (RAS) in the brain is a point of convergence of distinct angiotensinergic neural circuits which independently control fluid homeostasis, BP and MET. However, the mechanisms regulating BP and MET diverge at two important levels: 1) neural connectivity which dictates the resultant physiological outputs, and 2) intracellular signaling mechanisms which employ G proteins (Gαq vs Gαi) or β-arrestins. In the brain, AT1R traditionally couples to Gαq to regulate BP and Na intake. When dysregulated (or prolonged) AT1R Gαq signals can exert unfavorable effects such as increased BP, increased Na preference, and reduced resting metabolic rate. Project 1 will test the hypothesis that G protein and β-arrestin AT1R signaling differentially regulate BP vs fluid/Na intake in the forebrain, specifically the subfornical organ (SFO) and its connectome. Project 2 will test the hypothesis that AT1R coupling to Gαi within Agouti-related peptide (AgRP) neurons of the hypothalamic arcuate nucleus (ARC) requires β-arrestins, and that AgRP-melanocortin type 4 receptor (MC4R) neurotransmission from AT1R-expressing ARC AgRP neurons to the median preoptic nucleus (MPO) selectively mediates the stimulation of RMR, but not BP. Project 3 will test the hypothesis that early-life Na restriction programs a) increased fluid/electrolyte intake, CV sympathetic nervous activity (CV-SNA) and CV dysfunction susceptibility via enhanced excitatory AT1R-Gαq signaling within the SFO, and b) exaggerated thermogenic sympathetic nerve activity (MET-SNA) and RMR, thus causing growth failure, via inhibitory AT1R- β-arrestin-Gαi signaling within a specific subset of AgRP neurons located within the ARC that express AT1R (“Type 1” AgRP neurons). The ESI Project will test the hypotheses that renin-expressing neurons in the NuAm play a key role in autonomic balance and dysfunctional expression of renin in the NuAm leads to autonomic imbalance, and that the autonomic nervous system is regulated by the local generation and/or action of ANG in the NuAm. The projects will collectively provide conceptually innovative mechanistic insight into the neurocircuitry, and signal transduction cascades that contribute to cardiovascular and MET control physiology.


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: 2026 ( Subtotal = $2,753,400 )
2026	2026	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cardiovascular Diseases Research	000	1	8/19/2026	NEW	$2,753,400
														Subtotal = $2,753,400

Grand Total All Awards = $2,753,400

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Cellular and Molecular Mechanisms of Cardiometabolic Control by Angiotensin in the Brain: Role of AT1 Receptors and Biased Signaling

Award Number: P01HL180287

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2031

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