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

Inhibiting Adrenomedullin signaling to prevent mammalian brain endothelial cell abnormalities and brain arteriovenous malformation

Award Number: R03NS137135
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2024
PERIOD OF PERFORMANCE END DATE: 03/31/2027

Group Awards By:

View Award Description

Inhibiting Adrenomedullin signaling to prevent mammalian brain endothelial cell abnormalities and brain arteriovenous malformation - Project Summary/Abstract Maintenance of neurovascular health is critical for a properly functioning central nervous system (CNS). Neurovascular disorders not only affect the CNS vasculature – accompanying damage to CNS tissue can lead to neurological dysfunction, compromised quality of life, and even death. Brain arteriovenous malformation (AVM) is a human neurovascular disease characterized by enlarged, tortuous, often tangled vessels that shunt blood directly from artery to vein and promote abnormally high-velocity and high-pressure blood flow. Effective clinical treatments for brain AVM are limited to invasive surgical procedures; thus, there is a critical need for prevention and treatment strategies that can be delivered to patients pharmacologically. Recent sequencing data from a mouse model of brain AVM and from human brain AVM tissue independently showed increased Adrenomedullin (encodes a secreted vasodilatory peptide) expression in endothelial cells (ECs) from brain AVM, as compared to controls. This proposal will test whether inhibition of Adrenomedullin signaling, using a small molecule inhibitor in vivo and in vitro, can prevent EC abnormalities and features of brain AVM. We will use in vivo and in vitro approaches to examine whether Adrenomedullin signaling is required for vascular abnormalities associated with Rbpj-deficient brain AVM in mice and for cellular perturbations caused by RBPJ deficiency in cultured human brain ECs. The rationale is as follows: (i-ii) using a genetically inducible mouse model of brain AVM (endothelial deletion of Rbpj from postnatal day (P) 1) and an siRNA based in vitro system for cultured human brain ECs (si-RBPJ), we recently showed that endothelial Rbpj/RBPJ deficiency upregulates Adrenomedullin in both mouse (isolated at P14) and human brain ECs; (iii) we showed that Rbpj occupies chromatin regions mapping to Adrenomedullin, suggesting that Adrenomedullin is a direct binding target of Rbpj; (iv) published sequencing data from another lab showed increased Adrenomedullin expression in human brain AVM tissue. We will test the hypothesis that pharmacological inhibition of Adrenomedullin signaling prevents molecular and cellular abnormalities, including those that contribute to brain AVM, in Rbpj/RBPJ-deficient brain ECs. This hypothesis will be addressed in two specific aims that will determine whether inhibition of Adrenomedullin signaling, via in vivo or in vitro administration of the small-molecule inhibitor NSC16311, (Aim 1) attenuates brain AVM formation in endothelial-Rbpj deficient mice and (Aim 2) prevents cellular abnormalities in cultured, RBPJ-deficient human brain ECs. These studies will advance our long-term research objectives, which are to understand molecular and cellular mechanisms of brain AVM pathogenesis, including how different signaling molecules are involved, and to identify molecular targets that may lead to new, highly effective, pharmacologically based treatments for brain AVM. Our hope is to offer therapeutic options that alleviate symptoms of brain AVM, including neurological complications associated with this neurovascular disease.


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 = $0 )
2026	2025	OHIO UNIVERSITY	1 OHIO UNIVERSITY	ATHENS	OH	45701	ATHENS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	5/25/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $99,578 )
2025	2025	OHIO UNIVERSITY	1 OHIO UNIVERSITY	ATHENS	OH	45701	ATHENS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	4/14/2025	NON-COMPETING CONTINUATION	$75,500
2025	2025	OHIO UNIVERSITY	1 OHIO UNIVERSITY	ATHENS	OH	45701	ATHENS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	8/14/2025	SUPPLEMENT FOR EXPANSION	$24,078
														Subtotal = $99,578

Issue Date FY: 2024 ( Subtotal = $122,831 )
2024	2024	OHIO UNIVERSITY	1 OHIO UNIVERSITY	ATHENS	OH	45701	ATHENS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	9/10/2024	SUPPLEMENT FOR EXPANSION	$47,331
2024	2024	OHIO UNIVERSITY	1 OHIO UNIVERSITY	ATHENS	OH	45701	ATHENS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	2/19/2024	NEW	$75,500
														Subtotal = $122,831

Grand Total All Awards = $222,409

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Inhibiting Adrenomedullin signaling to prevent mammalian brain endothelial cell abnormalities and brain arteriovenous malformation

Award Number: R03NS137135

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2024

PERIOD OF PERFORMANCE END DATE: 03/31/2027

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer