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Stromal interaction molecule 1, immune cells, and vascular pathology in established hypertension

Award Number: R01HL151616
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2020
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Stromal interaction molecule 1, immune cells, and vascular pathology in established hypertension - ABSTRACT — The central mechanisms involved in hypertension-induced vascular pathology, a public health crisis, remain unknown. There is still a significant rate of adverse events in hypertensive patients prescribed these therapeutic and 2/3 of hypertensive patients are still resistant to these therapies. Thus, the critical unmet need is to identify mechanism based-treatable targets to rescue vascular function and structure in established hypertension. The pilot data showed that transferring healthy Treg into a mouse with established hypertension-induced by angiotensin II (Ang II) infusion improved vascular endothelial function and structure. We showed an increase in stromal interaction molecule 1 (STIM1) expression in Treg that could be responsible for Treg apoptosis by Nox2 and endoplasmic reticulum (ER) stress- dependent mechanisms. The overexpression of STIM1 in Treg cell caused Treg cell apoptosis. The depletion of dendritic cells in hypertensive mice improved arterial function and reduced arterial fibrosis and calcification through a reduction in INFγ and IL-1β release from dendritic cells and the inhibition of the ER stress in the endothelial cells. The central hypothesis is that STIM1 overexpression in Treg cells, through ROS and ER stress mechanism, cause Treg cells apoptosis and decrease IL-10 release, which increases dendritic cell activity leading to an increase in pro-inflammatory cytokines release (INFγ and IL-1β) and a decrease in anti-inflammatory IL-10 release causing the induction of the ER stress in endothelial cells and vascular pathology. To advance the Translational Sciences, we will test the hypothesis in two-kidney one- clip (2K1C) hypertensive mice Ang II-dependent. Specific Aim #1: To determine that in established hypertension, STIM1 expression is increased in Treg cells causing Treg cells apoptosis, a decrease in IL-10 release, and vascular pathology. Thus disrupting STIM1 expression in Treg cells would restore Treg cells number, IL-10 levels, and improve vascular endothelial function and reduce fibrosis and calcification in established hypertension. Specific Aim #2: To delineate that the decrease in IL-10 release, because of apoptosis in Treg, increases dendritic cells activity to release IFNγ and IL-1β and blunt IL-10 release, which causes vascular pathology via the induction of the ER stress mechanism in endothelial cells, and therefore depleting dendritic cells or manipulating the ER stress in endothelial cell improve vascular endothelial function and reduce fibrosis and calcification in established hypertension-induced by 2K1C. These studies are central to the mission of the NHLBI and address all Goals and multiple Strategies outlined in the NHLBI Strategic Plan. These studies will address 1) a need to further illuminate the biological mechanisms and pathological processes of the contribution of the immune cells, 2) The interaction between the immune system and the vascular system as a priority research topic and, 3) To advance the Translational Sciences, we will test the hypothesis in 2K1C mice model.


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 = $0 )
2025	2023	OLD DOMINION UNIVERSITY	HAMPTON BLVD	NORFOLK	VA	23529	NORFOLK CITY	USA	Cardiovascular Diseases Research	001	5	4/1/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$6,052
2025	2023	OLD DOMINION UNIVERSITY	735 FAIRFAX AVE STE 909	NORFOLK	VA	23507	NORFOLK CITY	USA	Cardiovascular Diseases Research	000	4	4/1/2025	NON-COMPETING CONTINUATION	-$6,052
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	OLD DOMINION UNIVERSITY	HAMPTON BLVD	NORFOLK	VA	23529	NORFOLK CITY	USA	Cardiovascular Diseases Research	002	5	7/24/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2024	2023	EASTERN VIRGINIA MEDICAL SCHOOL	735 FAIRFAX AVE STE 909C	NORFOLK	VA	23507	NORFOLK CITY	USA	Cardiovascular Diseases Research	000	4	6/27/2024	NON-COMPETING CONTINUATION	-$16,879
2024	2023	OLD DOMINION UNIVERSITY	HAMPTON BLVD	NORFOLK	VA	23529	NORFOLK CITY	USA	Cardiovascular Diseases Research	001	5	6/28/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$16,879
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $375,000 )
2023	2023	EASTERN VIRGINIA MEDICAL SCHOOL	735 FAIRFAX AVE STE 909C	NORFOLK	VA	23507	NORFOLK CITY	USA	Cardiovascular Diseases Research	000	4	7/7/2023	NON-COMPETING CONTINUATION	$375,000
														Subtotal = $375,000

Issue Date FY: 2022 ( Subtotal = $375,000 )
2022	2022	EASTERN VIRGINIA MEDICAL SCHOOL	735 FAIRFAX AVE STE 909C	NORFOLK	VA	23507	NORFOLK CITY	USA	Cardiovascular Diseases Research	000	3	7/28/2022	NON-COMPETING CONTINUATION	$375,000
														Subtotal = $375,000

Issue Date FY: 2021 ( Subtotal = $375,000 )
2021	2021	EASTERN VIRGINIA MEDICAL SCHOOL	358 MOWBRAY ARCH STE 305	NORFOLK	VA	23507	NORFOLK CITY	USA	Cardiovascular Diseases Research	000	2	7/22/2021	NON-COMPETING CONTINUATION	$375,000
														Subtotal = $375,000

Issue Date FY: 2020 ( Subtotal = $375,000 )
2020	2020	EASTERN VIRGINIA MEDICAL SCHOOL	358 MOWBRAY ARCH STE 305	NORFOLK	VA	23507	NORFOLK CITY	USA	Cardiovascular Diseases Research	000	1	6/30/2020	NEW	$375,000
														Subtotal = $375,000

Grand Total All Awards = $1,500,000

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Stromal interaction molecule 1, immune cells, and vascular pathology in established hypertension

Award Number: R01HL151616

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2020

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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