Decoding the molecular and cellular mechanisms of mutant kras-driven brain arteriovenous malformations

Active Project Grant Awarded Last action

Award ID
R01HL159159
Recipient
Awarding agency
Obligated
$7,525,645

Award facts

Assistance listing
93.837 Cardiovascular Diseases Research
Completion date 98% complete
Originally
Place of performance
Virginia, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Brain arteriovenous malformations (BAVMS) are composed of abnormal connections between arteries and veins that lack an intervening capillary network. As a result, high-pressure blood from feeding arteries shunts directly into veins. These vascular lesions become distended and highly remodeled, resulting in a tangle of enlarged blood vessels that are prone to rupture. Indeed, BAVMS are a leading cause of hemorrhagic stroke in children and young adults. All current treatment modalities for BAVMS, including surgery, embolization or radiation carry a significant risk of disability or death, and these options are not available for ~20% of bavm patients due to excessive risk. Because of these complications, alternative medical strategies with lower morbidities such as targeted pharmacological therapies are desperately needed. However, we first need a clear understanding of the biology underlying bavm development and maintenance. The majority of BAVMS occur sporadically without a family history of the disease. Using whole exome sequencing, we recently identified somatic, activating mutations in the kras gene, which encodes a gtpase that is involved in signal transduction. The identified mutations were confined to the endothelium and result in kras being locked in a GTP-bound 'on' state. Notably, we have established mouse and zebrafish models of endothelial-specific expression of mutant kras, which have revealed the sufficiency for these genetic lesions to drive disease. We have gone on to demonstrate, through transcriptional profiling of cultured cells and in vivo studies in zebrafish expressing mutant kras, that many kras-induced molecular and cellular changes require MEK/ERK activity. Much remains to be learned regarding the etiology of sporadic BAVMS and our cell culture, mouse and zebrafish models will enable US to define the molecular, cellular and morphological changes that are involved in the initiation and maintenance of BAVMS. We will utilize our expertise in animal models of BAVMS, imaging, cell biology, signaling and single-cell RNA sequencing, to gain unprecedented insight into the bavm disease process. This information will be leveraged for the design of pharmacological interventions to improve patient outcomes. Our proposal will: 1) define the threshold of kras mutant endothelial cells that can remodel vessels, 2) identify the vascular bed(S) that are susceptible to active kras expression, 3) determine how kras mutations impact hemodynamic signaling and bavm progression, 4) uncover the cell-autonomous and non-cell autonomous mechanisms of mutant kras, and 4) determine the requirement for kras and MEK activation for bavm maintenance in our pre-clinical models. Together, these studies will expand our understanding of bavm pathogenesis and will assess whether inhibition of the kras/MEK pathway may be a viable therapeutic target to pursue in human patients with bavm.

Transactions

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Original award $672,007
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Subawards

Subrecipient Amount Awarded
University Health Network Decoding the Molecular and Cellular Mechanisms of Mutant KRAS-driven Brain Arteriovenous Malformations $80,001
The Regents Of The University Of California. San Francisco As a co-Investigator on the current R01HL159159, Decoding the Molecular and Cellular Mechanisms of Mutant RAS-driven Brain Arteriovenous Malformations, my… $24,081

Quick answers

Who received award R01HL159159?

R01HL159159 was awarded to Rector & Visitors Of The University Of Virginia by National Heart Lung and Blood Institute (National Institutes of Health) on April 1, 2022.

How much is award R01HL159159 worth?

$7,525,645 has been obligated on R01HL159159.

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