Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Paracrine TNF signaling impairs endothelial TRPV4 microdomains in obesity

Award Number: R01HL142808
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2019
PERIOD OF PERFORMANCE END DATE: 05/31/2028

Group Awards By:

View Award Description

Paracrine TNF signaling impairs endothelial TRPV4 microdomains in obesity - ABSTRACT Endothelial calcium signaling mechanisms regulate vascular function and blood pressure. In obesity, impaired endothelial calcium signaling results in the loss of endothelium-mediated dilation and elevation of blood pressure. The goal of this application is to identify targetable abnormalities in endothelial calcium signaling mechanisms in obesity. Our recent studies show that TRPV4 channels, a crucial calcium entry pathway in endothelial cells, lower blood pressure under normal conditions. Moreover, increased formation of peroxynitrite, a reactive nitrogen species, reduces the activity of endothelial TRPV4 channels and elevates blood pressure in obesity. Tumor necrosis factor (TNF), an inflammatory cytokine, is a well-known promoter of cellular peroxynitrite formation. Our preliminary data show that TNF is selectively upregulated in the vascular smooth muscle cells in obesity. Therefore, we will determine the role of smooth muscle cell TNF and endothelial cell TNF receptor I (TNFRI) in increasing endothelial peroxynitrite levels and impairing endothelial calcium signaling in diet-induced obesity. We will use newly developed cell-specific knockout mice for TNF and TNFRI in combination with peroxynitrite and TRPV4 channel measurements in small arteries. Also, mineralocorticoid receptor (MR) activation has been linked with increased TNF levels and endothelial dysfunction. Therefore, we will delineate how vascular MR- induced TNF production impairs endothelial calcium signaling and elevates blood pressure in obesity. We will use smooth muscle cell-specific MR knockout mice to determine the role of smooth muscle MR in increasing TNF production and impairing endothelial function in obesity. Finally, we will determine the contribution of smooth muscle TRPV4 channels and related pathways in increasing TNF production in obesity. Studies in skeletal muscle arteries of obese patients will establish the clinical relevance of our findings on vascular MR-TNF-TNFRI signaling axis in obesity. Collectively, these fundamental and clinically relevant studies will fill major gaps in our understanding of endothelial calcium signaling abnormalities in obesity and identify potential therapeutic targets for rescuing endothelial function.


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 = $616,900 )
2026	2026	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	000	8	5/18/2026	NON-COMPETING CONTINUATION	$616,900
														Subtotal = $616,900

Issue Date FY: 2025 ( Subtotal = $681,460 )
2025	2025	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	001	7	6/30/2025	NON-COMPETING CONTINUATION	$681,460
2025	2023	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	000	5	2/17/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $681,460

Issue Date FY: 2024 ( Subtotal = $697,430 )
2024	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	001	6	6/10/2024	COMPETING CONTINUATION	$69,744
2024	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	000	6	4/1/2024	COMPETING CONTINUATION	$627,686
														Subtotal = $697,430

Issue Date FY: 2023 ( Subtotal = $476,925 )
2023	2023	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	000	5	6/5/2023	NON-COMPETING CONTINUATION	$476,925
														Subtotal = $476,925

Issue Date FY: 2022 ( Subtotal = $476,925 )
2022	2022	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	000	4	5/28/2022	NON-COMPETING CONTINUATION	$476,925
														Subtotal = $476,925

Issue Date FY: 2021 ( Subtotal = $476,925 )
2021	2021	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	000	3	6/8/2021	NON-COMPETING CONTINUATION	$476,925
														Subtotal = $476,925

Issue Date FY: 2020 ( Subtotal = $476,925 )
2020	2020	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	000	2	6/19/2020	NON-COMPETING CONTINUATION	$476,925
														Subtotal = $476,925

Issue Date FY: 2019 ( Subtotal = $482,908 )
2019	2019	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	000	1	5/3/2019	NEW	$482,908
														Subtotal = $482,908

Grand Total All Awards = $4,386,398

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Paracrine TNF signaling impairs endothelial TRPV4 microdomains in obesity

Award Number: R01HL142808

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2019

PERIOD OF PERFORMANCE END DATE: 05/31/2028

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer