The alpha arrestin family includes the best studied member, Txnip, and five other proteins with unknown functions. Txnip was originally considered a regulator of vascular redox state. Because Txnip is induced by hyperglycemia, and Txnip can inhibit thioredoxin, many investigators have proposed that hyperglycemia Induces oxidative stress through Txnip-mediated inhibition of thioredoxin. However, compelling evidence has now emerged that Txnip is a critical regulator of diverse signaling events relevant to vascular disease. Because Txnip can form a mixed disulfide complex with reduced thioredoxin (but not oxidized thioredoxin),Txnip may function as a redox-sensitive signaling regulator rather than simply as an inhibitor of thioredoxin. Our preliminary data show that Txnip is an important mediator of glucose and lipid metabolism, insulin sensitivity, adipogenesis, and energy balance. Here we present data supporting the central hypothesis that Txnip is a critical intracellular signaling regulator, and that Txnip's functions are unlikely to be solely due to inhibition of thioredoxin. We propose three Alms that will define the role of Txnip in endothelial cells:
AIM 1. To define the role of the interaction of Txnip and thioredoxin in the inflammatory response of endothelial cells. Here we will test the hypothesis that the role of Txnip In the regulation of the vascular inflammatory response is dependent on the specific molecular interaction with thioredoxin through an Intermolecular disulfide bond.
AIM 2. To define structure-function relations of Txnip. We present preliminary data that specific domains of Txnip regulate glucose metabolism;using the known structure of beta arrestins, we will define specific regions of Txnip as well as other alpha arrestins that regulate glucose metabolism and the endothelial shear stress response.
AIM 3 :To test the hypothesis that Txnip regulates metabolism in vivo via a PPAR-gamma dependent mechanism in endothelial cells. We will determine whether Txnip's ihipact on PPAR-gamma function is dependent on thioredoxin and test the hypothesis that Txnip causally influences PPAR-gamma function in vivo. Finally, we will explore in vivo the concept that Txnip impacts PPAR-gamma function to mediate whole body metabolic regulation through endothelial cell expression.

Public Health Relevance

Many cardiovascular diseases are characterized by vascular inflammation and by damage to the endothelial cells that line blood vessels, arising from the oxidation of critical proteins in these cells. This research project studies a protein called Txnip, which regulates protein oxidation in vascular cells and other tissues. Txnip is involved In the metabolism of glucose and undergoes regulation by pathways that are altered in diabetes.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL048743-20
Application #
8375109
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
20
Fiscal Year
2012
Total Cost
$410,550
Indirect Cost
$180,550
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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