Colorado PROFILES, The Colorado Clinical and Translational Sciences Institute (CCTSI)
Keywords
Last Name
Institution

Contact Us
If you have any questions or feedback please contact us.

REGULATION OF BETA-ADRENERGIC RECEPTOR MRNA STABILITY


Collapse Biography 

Collapse Overview 
Collapse abstract
Heart failure is an increasingly prevalent disease syndrome with a poor long-term prognosis. As a result of progressive myocardial dysfunction, the adrenergic nervous system and the renin-angiotensin system are abnormally activated. One consequence of persistently elevated adrenergic drive is the activation of multiple compensatory physiological and cellular mechanisms producing down-regulation and desensitization of the myocardial beta-adrenergic receptor (AR) pathways. To investigate the mechanisms involved in beta-AR down-regulation, my previous work, and that of others, has focused on measuring the abundance of mRNAs encoding beta1- and beta2-ARs. Although mechanisms responsible for regulation of adrenergic receptor mRNAs have not been investigated extensively, it is becoming increasingly clear that analogous to protooncogenes and cytokines, up- and down-regulation of beta-AR mRNAs by stabilization/destabilization of the mRNA may be an important regulatory control point. Yet, only very preliminary data exist for the relationship between mRNA stability and any component of the G-protein linked receptor pathways. Recently, we have found that beta-AR mRNA interacts with an Mr 35,000 protein. This protein shares several important characteristics with other mRNA binding proteins that preferentially interact with AU-rich regions, and have been shown to be involved in the targeting of mRNA for rapid turnover. More importantly, the apparent abundance of this mRNA binding protein is highly regulated, being increased by stimulation of pathways that down-regulate beta-AR and decreased by stimulation of pathways that up-regulate or uncouple beta-AR.

The essence of this proposal is to begin to explore, in depth, the cellular mechanisms by which adrenergic receptor mRNA abundance is controlled by the process of mRNA stability. To perform this objective, I will focus on: domain specificity of beta-AR mRNA binding proteins, map regions of beta-AR mRNA which may act as stabilizing or destabilizing elements, determine the effect of the extent of polyadenylation on beta-AR mRNA stability, develop a cell-free, in vitro, mRNA decay system, and begin to purify and characterize mRNA binding proteins that bind to beta- AR mRNA.

The results of these studies should extend our knowledge in two important areas. First, understanding in greater detail the mechanisms of regulation of beta-AR mRNA stability will help more clearly define a major phenotype of heart failure at a molecular level. Second, what can be learned from beta-AR model systems often serves as a basis for extension to other G- protein coupled receptors.
Collapse sponsor award id
R29HL051239

Collapse Time 
Collapse start date
1994-01-01
Collapse end date
1998-12-31

Copyright © 2022 The Regents of the University of Colorado, a body corporate. All rights reserved. (Harvard PROFILES RNS software version: 2.11.1)