This application represents a request for an extension of this MERIT Award. The central hypothesis of this award is that glutathione peroxidase-3 (GPx-3) is a principal determinant of extracellular hydrogen peroxide flux from the endothelial cell, and a key regulator of the transmemrane cycling and intracellular actions of hydrogen peroxide. The key scientific accomplishments of this first phase of the award include the identification of essential regulatory determinants of GPx-3, a selenoprotein with complex and unique translational requirements;demonstration of the cofactor activation of GPx-3 catalysis by heparin via a unique polyanionic glycosaminoglycan binding site in the solvent-exposed carboxyterminal tail;the development of a GPx-3 null mouse and the characterization of its vascular and endothelial dysfunction, including a propensity to platelet-dependent thrombosis, the latter recapitulating our work in human populations of subjects with arterial ischemic or cerebral venous strokes;the identification of plasma membrane channels and transporters for hydrogen peroxide and nitric oxide;and the demonstration that mitochondria are a key source of hydrogen peroxide that can be modulated by GPx-3's intracellular counterpart, GPx-1, as well as a unique microRNA, miR210, in part responsible for the Pasteur effect. In this extension of the award, we plan to continue to pursue the same central hypothesis, but will do so in the setting of hypoxia because of the differential effect of hypoxia on GPx-3 (increases) and GPx-1 (decreases), and because of the greater role played by uncoupled mitochondria on hydrogen peroxide production under hypoxic compared with normoxic conditions. We will pursue this goal via three specific aims. First, we will examine the effect of hypoxia on GPx-3 expression, selenium uptake, and the selenoprotein synthesis hierarchy (in renal tubular cells, the primary source of plasma GPx-3 in mammals). Second, we will examine the interactions between GPx-3 and GPx-1 on endothelial hydrogen peroxide production under hypoxic conditions and its consequences for hydrogen peroxide-dependent endothelial signaling. Third, we wll examine the effects of GPx-3 on endothelial function in vivo under hypoxic conditions. These studies should complement prior work conducted during this award, and provide additional useful insights into the role of GPx-3 in the adaptive response to hypoxic stress In the endothelium.

Public Health Relevance

In thls program, we focus on an extracellular enzyme that is a principal regulator of oxidant stress in the vascular compartment, glutathione peroxidase-3. We have studied this molecule across the translational spectrum, having shown its importance as a risk factor for ischemic stroke, now with mechanistic and genetic models supporting this association. We continue to pursue studies of the role of this enzyme in modifying endothelial function under hypoxia, a condition that is common to many vascular diseases with important consequences for endothelial function. These studies should provide unique insights into the regulation of vascular oxidant stress in health and disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37HL061795-17
Application #
8598830
Study Section
Special Emphasis Panel (NSS)
Program Officer
Fleg, Jerome
Project Start
1998-09-30
Project End
2016-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
17
Fiscal Year
2014
Total Cost
$378,344
Indirect Cost
$153,344
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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