Project Details

Description

DESCRIPTION (provided by applicant): In this proposal we will determine the role of Ras GTPase-activating protein (RasGAP) in regulating microRNA-1 (miR-1) during cardiac hypertrophy. MiR-1 is a post- transcriptional regulator of gene expression that is acutely down-regulated upon induction of hypertrophy by work overload, growth factors, or RasGAP, an outcome that is necessary for myocyte growth. Our preliminary data show that RasGAP SH3-binding protein (G3BP) binds miR-1 in a RasGAP- and Akt-dependent manner. We hypothesize that hypertrophic stimuli induce Akt-mediated G3BP phosphorylation and its subsequent recruitment by RasGAP-filamin complex. This brings it into close proximity to miR-1, where it binds and hydrolyzes premature miR-1. Subsequently, down-regulation of miR- 1 results in upregulation of its targets that include: RasGAP, Cdk9, fibronectin, endothelin, and insulin-like growth factor, among others. These genes play a critical role in the development of cardiac hypertrophy. Thus, our Aims are: 1) to study the mechanism of RasGAP-mediated down-regulation of miR-1 during myocyte hypertrophy. For this aim we will utilize cultured myocytes in conjunction with recombinant cDNA, adenoviruses, and promoter constructs, using stretch as a hypertrophic stimulus to: a. examine the role of G3BP in post-transcriptional regulation of miR-1, b. examine the role of Akt in RasGAP-G3BP-regulated miR-1 stability, c. examine the role of filamin-C in recruitment of RasGAP-G3BP, d. examine the effect of hypertrophy and the RasGAP- activated pathway on transcriptional vs. post-transcriptional regulation of miR-1. Aim 2) to study the role of RasGAP and miR-1 during cardiac hypertrophy in a mouse model.
StatusFinished
Effective start/end date1/1/0412/31/15

Funding

  • National Heart, Lung, and Blood Institute: $311,000.00
  • National Heart, Lung, and Blood Institute: $390,000.00
  • National Heart, Lung, and Blood Institute: $390,000.00
  • National Heart, Lung, and Blood Institute: $311,000.00
  • National Heart, Lung, and Blood Institute: $390,000.00
  • National Heart, Lung, and Blood Institute: $303,692.00
  • National Heart, Lung, and Blood Institute: $198,067.00
  • National Heart, Lung, and Blood Institute: $188,033.00
  • National Heart, Lung, and Blood Institute: $50,880.00
  • National Heart, Lung, and Blood Institute: $294,884.00

ASJC

  • Cardiology and Cardiovascular Medicine
  • Genetics
  • Molecular Biology
  • Cell Biology

Fingerprint

Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.