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Neuroimmune mechanisms underlying electroacupuncture effect on vascular function

Award Number: R01AT011306
ORGANIZATION: CENTER FOR DRUG EVALUATION AND RESEARCH, NIH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/16/2021
PERIOD OF PERFORMANCE END DATE: 07/31/2026

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Neuroimmune mechanisms underlying electroacupuncture effect on vascular function - PROJECT SUMMARY Hypertension (HTN) is the most significant modifiable risk factor for cardiovascular disease and involves multiple pathways including those in the neuroendocrine and immune systems. Antihypertensive drugs manage HTN but do not address the central sympathetic and inflammatory pathways and approximately 50% of hypertensive (HTNive) patients do not have their blood pressure (BP) controlled. The World Health Organization has suggested acupuncture for HTN; however, prior clinical trials utilizing acupuncture have shown modest or null outcomes and not achieved clinically meaningful reductions in BP. These conflicting outcomes result from the lack of a mechanistic-based approach to using electroacupuncture (EA), a form of neurostimulation. The reasons for inadequate treatment and BP control are complex, but one reason for this therapeutic misalignment may be an incomplete understanding of the mechanisms underlying the development and progression of HTN including autonomic dysfunction and resulting low-grade inflammation. Using neuroanatomical mapping, phenotyping, and recording of neurophysiological responses that correspond to neuromodulatory mechanisms underlying effects of EA, we successfully selected specific acupoints that in combination (or combined (c)EA) show complementary mechanisms of sympathoinhibition and parasympathoexcitation and not only reduce BP to clinically meaningful levels but also improve underlying autonomic dysfunction and low-grade inflammation. Our proposed study addresses one of NCCIH’s top priorities, “Determine and analyze the neural pathways by which acupuncture exerts its therapeutic effects.” Our strong preliminary data, from Dahl Salt Sensitive (DSS) HTNive rats, show that our targeted acupoints, which simultaneously activate afferents in the median, tibial, and deep peroneal nerves then modulate CNS regulation by activation of neurons in the nucleus of tractus solitarius (NTS), dorsal motor nucleus of the vagus (DMV). This modulation resulted in an increase in descending peripheral parasympathetic splenic activity. Treatment with cEA also reduced presympathetic neuronal and splanchnic sympathetic nerve activities. In this study, we will investigate if cEA treatment leads to BP reduction by improving autonomic dysfunction and decreasing inflammation through the neural mechanistic pathways we have preliminarily discovered. Our main aim is to assess mechanisms of the BP lowering effect of cEA in HTNive animals and then validate the improvement in autonomic indices by translating it in mild-moderative HTNive patients. We plan to achieve this by: 1) direct assessment of the effect of cEA on neurons in the hypothalamic and brainstem regions controlling sympathetic and parasympathetic balance including NTS, DMV, paraventricular nucleus, and rostral ventrolateral medulla, as well as sympathetic and parasympathetic efferent activities; 2) investigating if cEA reduces inflammation through acetylcholinergic receptors (AChR) activity in DSS HTNive rats; and 3) using a parallel 2x2 factorial design in a human randomized control study, primarily assess effects of cEA compared to sham-EA (as well as secondarily compare sympathoinhibitory-EA, anti-inflammatory-EA, and cEA) on physiological alterations in autonomic function and secondarily on chronic inflammation. If successful, this study would address the mechanistic basis for the effects of EA as a therapeutic option for HTNive patients who are not at optimal BP goals with conventional therapy alone.


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 = $503,389 )
2025	2025	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Research and Training in Complementary and Integrative Health	000	5	7/24/2025	NON-COMPETING CONTINUATION	$503,389
														Subtotal = $503,389

Issue Date FY: 2024 ( Subtotal = $598,782 )
2024	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Research and Training in Complementary and Integrative Health	000	4	9/9/2024	NON-COMPETING CONTINUATION	$598,782
														Subtotal = $598,782

Issue Date FY: 2023 ( Subtotal = $644,220 )
2023	2023	UNIVERSITY OF CALIFORNIA, IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Research and Training in Complementary and Integrative Health	000	3	8/9/2023	NON-COMPETING CONTINUATION	$644,220
														Subtotal = $644,220

Issue Date FY: 2022 ( Subtotal = $662,479 )
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Research and Training in Complementary and Integrative Health	001	2	8/31/2022	NON-COMPETING CONTINUATION	$662,479
2022	2021	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Research and Training in Complementary and Integrative Health	000	1	8/30/2022	NEW	$0
														Subtotal = $662,479

Issue Date FY: 2021 ( Subtotal = $679,931 )
2021	2021	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Research and Training in Complementary and Integrative Health	000	1	8/16/2021	NEW	$679,931
														Subtotal = $679,931

Grand Total All Awards = $3,088,801

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Neuroimmune mechanisms underlying electroacupuncture effect on vascular function

Award Number: R01AT011306

ORGANIZATION: CENTER FOR DRUG EVALUATION AND RESEARCH, NIH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/16/2021

PERIOD OF PERFORMANCE END DATE: 07/31/2026

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