Neurovascular protection by adropin in acute neural injury from subarachnoid hemorrhage

Active Project Grant Awarded Last action

Award ID
R01NS124620
Recipient
Awarding agency
Obligated
$2,645,214

Award facts

Completion date 84% complete
Place of performance
Gainesville, FL 32611, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Acute neural injury from subarachnoid hemorrhage (SAH)-associated cerebral infarction occurs in 30-40% of patients who survive the initial hemorrhage, leads to death and disability, and most strongly correlates with 3- month outcome. There is also a significant rate of long-term cognitive deficits. Current understanding of the pathophysiology of post-SAH cerebral infarction points to injury cascades involving decreased nitric oxide (no) bioavailability and oxidative stress. Under normal conditions, no signaling pathways regulate cerebral blood flow by mediating cerebral vasodilation and inhibiting platelet adhesion. However, with SAH, red blood cells lyse and release hemoglobin, which is a spasmogenic. Hemoglobin scavenges no; stimulates production of a nitric oxide synthase (NOS) inhibitor (adma); and generates reactive oxygen species (ROS) and nitrogen species (RNS). We believe the recently-identified peptide hormone adropin is a promising therapeutic target for post-SAH cerebral infarction. Our group and others have shown adropin is abundantly expressed in the brain, regulates the endothelial nitric oxide synthase (enos) pathway, correlates with markers of oxidative stress, and reduces brain endothelial permeability in response to simulated ischemia. Our hypothesis is that adropin confers protection against acute neural injury from post-SAH cerebral infarction. Our overall goal in this proposal is to demonstrate the protective role of adropin in SAH and investigate the underlying molecular and cellular mechanisms of this protection. Our preliminary data support this hypothesis by showing that SAH decreases brain adropin expression, and that endogenous adropin overexpression by transgenic mice with a SS-actin-driven adropin transgene (adrtg) or treatment with synthetic adropin in the SAH model reduces cerebral edema, preserves tight junction protein expression, abolishes microthrombosis, increases enos phosphorylation, prevents cerebral vasospasm, and inhibits neuronal apoptosis. Aim 1 is to determine whether adropin confers protection against acute neural injury after SAH when given in a clinically translatable timepoint after SAH. In aim 2, we will study mediators that regulate enho gene expression in the setting of SAH. In aim 3, we will study whether adropin neurovascular protection is mediated via enos activity. We expect this study will provide novel knowledge on adropin-mediated protection against acute neural injury after SAH. The significance of this study is that IT is directly translatable and the first to investigate the fundamentals of adropin regulation in brain endothelial cells after SAH. This study will provide the preclinical data for a phase 1/2 human clinical trial in SAH patients.

Transactions

Action Obligated Date
Amendment $374,407
Amendment $375,018
Amendment $364,307
Amendment $379,548
Amendment $379,548
Amendment $386,193
Original award $386,193

Subawards

Subrecipient Amount Awarded
Saint Louis University My primary role in the project will be to provide guidance and feedback to the PIs on adropin mouse models, as well as assist in data analysis and… $18,391
Saint Louis University My primary role in the project will be to provide guidance and feedback to the PIs on adropin mouse models, as well as assist in data analysis and… $73,564

Quick answers

Who received award R01NS124620?

R01NS124620 was awarded to University Of Florida by National Institute of Neurological Disorders and Stroke (National Institutes of Health) on August 15, 2022.

How much is award R01NS124620 worth?

$2,645,214 has been obligated on R01NS124620.

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