Tuesday, August 19, 2025 8/19/2025

Angiopoietin-2 Signaling Targeted Therapeutics for Arteriovenous Malformations

Award Number: R01HL163196
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2022
PERIOD OF PERFORMANCE END DATE: 03/31/2026

Group Awards By:

View Award Description

Angiopoietin-2 Signaling Targeted Therapeutics for Arteriovenous Malformations - PROJECT SUMMARY Hereditary Hemorrhagic Telangiectasia (HHT) is a vascular genetic disorder characterized by enlarged, leaky small vessels (telangiectasias) and inappropriate, fragile connections between arteries and veins called arteriovenous malformations (AVMs). HHT patients develop AVMs in a specific subset of major organs, which can rupture causing severe hemorrhage and anemia, as well as aneurysms, stroke and even death. Causes of HHT are linked to the Transforming Growth Factor-beta (TGF-beta) signaling pathway, with over 90% of patients exhibiting heterozygous loss-of-function mutations in the Activin receptor-like kinase 1 (Acvrl1/Alk1) or Endoglin (Eng) co-receptors, or the downstream transcription factor, Smad-related protein 4 (Smad4). Despite knowing the causative mutations, a significant gap remains in our understanding of the immediate TGF-beta downstream signaling components responsible for HHT pathologies. Furthermore, no cure is currently available for HHT. We have found that directly downstream of Alk1, Eng and Smad4 loss-of-function, the angiogenic factor and antagonistic ligand to the Tie2 receptor, angiopoietin-2 (Angpt2/ANG2), is transcriptionally elevated to trigger HHT vascular pathologies; ANG2 neutralization efficiently reduced AVM pathology in two HHT mouse models. In addition, loss of Alk1 signaling led to a robust and consistent transcriptional and signaling inhibition of Tek/Tie2. Together, these observations strongly support the working model that ANG2 is elevated and Tie2 signaling is repressed during the pathogenic process of AVM development in HHT. Moreover, the metabolic PI3K/Akt/mTOR pathway is deregulated in HHT to sustain AVM development, however its connection to ANG2 pro-AVM signals is unclear. Using mouse models of the different genetic forms of HHT and primary endothelial cells (ECs), we have obtained strong pilot data indicating that ANG2-Tie2 deregulations, working in concert with enhanced FoxO1 transcriptional activity and sequential overactivation of the mTOR pathway via CXCR4 chemokine signaling, drive HHT phenotypes. The central objective of this application is to answer 3 fundamental questions: 1) how does ANG2 elevation and Tie2 signaling repression direct AVM pathogenesis, 2) what is the mechanism by which mTOR overactivation is controlled by ANG2-Tie2 signaling deregulations and 3) are approaches targeting ANG2 and the newly identified ANG2-regulated pathogenic signaling cascade universally effective in treating HHT vascular pathologies? We will address these topics by testing the following specific aims: 1) Assess ANG2 and Tie2 signaling deregulations in the most physiologically affected organs and determine if ANG2 inhibition universally blocks vascular pathologies in HHT mouse models; 2) Determine FoxO1 contributions to ANG2 and CXCR4 elevations and HHT vascular pathologies; and 3) Test if TGF-beta-Tie2- FoxO1-mediated CXCR4 elevations drive mTOR activation. These studies will advance our mechanistic understanding of AVM pathogenesis and uncover new potential targets for treating of HHT.


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 = $671,700 )
2025	2025	THE ADMINISTRATORS OF TULANE EDUCATIONAL FUND	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Cardiovascular Diseases Research	001	4	8/15/2025	NON-COMPETING CONTINUATION	$67,171
2025	2025	THE ADMINISTRATORS OF TULANE EDUCATIONAL FUND	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Cardiovascular Diseases Research	000	4	2/19/2025	NON-COMPETING CONTINUATION	$604,529
														Subtotal = $671,700

Issue Date FY: 2024 ( Subtotal = $664,047 )
2024	2024	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Cardiovascular Diseases Research	000	3	3/5/2024	NON-COMPETING CONTINUATION	$609,839
2024	2024	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Cardiovascular Diseases Research	001	3	6/20/2024	NON-COMPETING CONTINUATION	$54,208
														Subtotal = $664,047

Issue Date FY: 2023 ( Subtotal = $683,964 )
2023	2023	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Cardiovascular Diseases Research	000	2	3/7/2023	NON-COMPETING CONTINUATION	$683,964
														Subtotal = $683,964

Issue Date FY: 2022 ( Subtotal = $702,416 )
2022	2022	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Cardiovascular Diseases Research	000	1	3/7/2022	NEW	$702,416
														Subtotal = $702,416

Grand Total All Awards = $2,722,127

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Angiopoietin-2 Signaling Targeted Therapeutics for Arteriovenous Malformations

Award Number: R01HL163196

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2022

PERIOD OF PERFORMANCE END DATE: 03/31/2026

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer