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Modeling second hit somatic mutations in HHT to uncover mechanisms of vascular pathologies and assess therapeutic strategies.

Award Number: R01HL187693
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/05/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2030

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Modeling second hit somatic mutations in HHT to uncover mechanisms of vascular pathologies and assess therapeutic strategies. - PROJECT SUMMARY Hereditary Hemorrhagic Telangiectasia (HHT) is a genetic disorder characterized by inappropriate connections between arteries and veins called arteriovenous malformations (AVMs) and leaky small vessels (telangiectasias). AVMs form in major organs (brain, liver and lung) and can rupture causing severe hemorrhage and anemia, as well as aneurysms, stroke and death. HHT affects ~1 in 5000 people and the genetic causes are linked to the Transforming Growth Factor-ß signaling pathway, with >90% of patients carrying heterozygous loss-of-function mutations in the Activin receptor-like kinase 1 (ACVRL1/ALK1) or Endoglin (ENG) co-receptors, or the transcription factor, Smad-related protein 4 (SMAD4). Despite knowing the disease-causing mutations, our molecular understanding of HHT pathologies, including AVMs and especially vascular leakage, remains insufficient. Due to this knowledge gap, it is crucial that we uncover the disease mechanisms and identify therapeutic targets because a cure for HHT does not exist. Genetic analysis indicates HHT lesions can form via loss-of-heterozygosity (LOH) whereby a second somatic mutation of the functional allele leads to complete loss of gene function in some endothelial cells. However, current HHT models do not accurately depict an LOH setting and thus, there is an incomplete understanding of how AVMs and vessel instability arise. We created Smad4 and Eng LOH-HHT mouse models to assess LOH contributions on HHT pathologies. Our preliminary data strongly indicates compromised vascular integrity in LOH-HHT mice leading to increased blood vessel permeability, in addition to a potential regulator of this process (CDH13). Research on vascular leakiness is critical because bleeding is a chronic and debilitating issue for HHT patients, yet basic research on vessel integrity is sorely lacking. Anti-VEGFA drugs have shown beneficial effects for reducing bleeding, however some patients do not respond and the impacts of inhibiting VEGF signaling on AVMs is unclear. In this regard, ANG2 is a strong clinical candidate: excess ANG2 is linked to vascular leakage in several ocular diseases, while our prior data demonstrated ANG2 inhibition could ameliorate AVM formation. We hypothesize that targeting ANG2 and VEGFA may provide a robust avenue to combat AVM development and vessel instability. The central objective of this application is to answer 3 fundamental questions: 1) how does LOH contribute to the development of AVMs; 2) what are the mechanistic drivers of vascular leakiness in HHT; 3) do dual approaches targeting ANG2 and VEGFA provide superior effectiveness to prevent, stabilize or regress AVM formation and bleeding? We will address these topics by testing the following specific aims: 1) Evaluate the impact of LOH on AVM formation; 2) Characterize vascular permeability and bleeding and assess CDH13 contributions; 3) Assess ANG2 and VEGFA based therapeutics on HHT pathologies. Together, this investigation will utilize new models to more accurately represent the pathobiology of HHT patients, thereby enhancing our knowledge on the pathogenic mechanisms of AVM formation and bleeding, leading to therapeutic advancements for 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: 2026 ( Subtotal = $565,442 )
2026	2026	THE ADMINISTRATORS OF TULANE EDUCATIONAL FUND	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Cardiovascular Diseases Research	000	1	9/5/2026	NEW	$565,442
														Subtotal = $565,442

Grand Total All Awards = $565,442

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Modeling second hit somatic mutations in HHT to uncover mechanisms of vascular pathologies and assess therapeutic strategies.

Award Number: R01HL187693

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/05/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2030

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