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Mechanisms of Stress-Induced Hypertension

Award Number: R01HL139523
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/28/2017
PERIOD OF PERFORMANCE END DATE: 12/31/2022

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Mechanisms of Stress-Induced Hypertension - Mechanisms of stress-Induced Persistent Hypertension PROJECT SUMMARY Prolonged and persistent stress is a known risk factor in the development of hypertension. Previous stud- ies have shown that in borderline hypertension, chronic stress-induced increases in arterial blood pressure last for a long period after termination of stress paradigms. However, the underlying mechanisms remain unknown. Chronic stress activates corticotropin-releasing hormone (CRH)-expressing neurons in the hypo- thalamus and central nucleus of the amygdala (CeA), which play a key role in regulating autonomic and cardiovascular functions during psychological stress, fear, and anxiety. The overall objective of our project is to determine the role of CeA-CRH neurons in the development of persistent hypertension and the mech- anisms involved. Our preliminary data showed that selectively inhibiting CeA-CRH neurons through a chemogenetic approach prevented chronic stress-induced hypertension in borderline hypertensive rats (BHRs) and that hyperactivity of CeA-CRH neurons was due to a reduction of K+ channel activity resulting from stress-induced increases in histone deacetylase (HDAC) activity. Our pilot study also showed that in- hibition of HDAC activity in the CeA in chronically stressed rats restored K+ expression and decreased fir- ing activity of CeA-CRH neurons. In this proposal, we will test the central hypothesis that hyperactivity of CeA-CRH neurons is responsible for stress-induced hypertension in BHRs and that a reduction in K+ channel activity caused by stress-induced upregulation of HDAC leads to hyperactivity of CeA-CRH neu- rons in stress-induced hypertension. Because the chronic unpredictable mild stress rat model closely re- sembles precipitation of depression by chronic and low-grade stressors in humans, this model will be used to test the hypothesis. We have 4 specific aims: We will attempt to determine the role of CeA-CRH neurons in the sustained hypertension in chronically stressed BHRs (aim 1), determine the role of CeA-CRH neu- rons in regulating blood pressure and sympathetic outflow in chronically stressed BHRs (aim 2), determine the role of K+ channels in the CeA in hyperactivity of CeA-CRH neurons and heightened sympathetic out- flow in chronically stressed BHRs (aim 3), and identify the epigenetic mechanisms involved in long-lasting downregulation of K+ channels in chronically stressed BHRs (aim 4). Our proposal is innovative because findings from our proposal are expected to provide novel information about the cellular and molecular mechanisms responsible for stress-induced persistent hypertension in borderline hypertension. This new information is significant because it may provide an important rationale for development of new strategies to treat neurogenic 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: 2024 ( Subtotal = $0 )
2024	2021	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Cardiovascular Diseases Research	001	4	11/9/2023	NON-COMPETING CONTINUATION	$0
2024	2021	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Cardiovascular Diseases Research	000	4	11/9/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = -$5,927 )
2022	2018	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cardiovascular Diseases Research	000	1	6/29/2022	NEW	-$5,927
														Subtotal = -$5,927

Issue Date FY: 2021 ( Subtotal = $410,631 )
2021	2021	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Cardiovascular Diseases Research	000	4	12/30/2020	NON-COMPETING CONTINUATION	$369,569
2021	2021	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Cardiovascular Diseases Research	001	4	5/15/2021	NON-COMPETING CONTINUATION	$41,062
														Subtotal = $410,631

Issue Date FY: 2020 ( Subtotal = $411,736 )
2020	2020	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Cardiovascular Diseases Research	001	3	1/31/2020	NON-COMPETING CONTINUATION	$20,589
2020	2020	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Cardiovascular Diseases Research	000	3	1/13/2020	NON-COMPETING CONTINUATION	$391,147
														Subtotal = $411,736

Issue Date FY: 2019 ( Subtotal = $433,664 )
2019	2019	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Cardiovascular Diseases Research	001	2	12/31/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$433,664
2019	2019	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Cardiovascular Diseases Research	003	2	1/24/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$200,382
2019	2018	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Cardiovascular Diseases Research	002	1	1/24/2019	NEW	-$200,382
2019	2018	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Cardiovascular Diseases Research	000	1	12/31/2018	NEW	$0
														Subtotal = $433,664

Issue Date FY: 2018 ( Subtotal = $529,512 )
2018	2018	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Cardiovascular Diseases Research	000	1	12/7/2017	NEW	$529,512
														Subtotal = $529,512

Grand Total All Awards = $1,779,616

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Mechanisms of Stress-Induced Hypertension

Award Number: R01HL139523

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/28/2017

PERIOD OF PERFORMANCE END DATE: 12/31/2022

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