CARDIAC GENE TRANSFER--HYPERTENSION RESPONSIVE ELEMENTS

Project: Research project

Project Details

Description

Systemic hypertension is a major public health problem in the United
States. The mechanisms by which it affects an organs, such as the heart,
remain poorly understood at the molecular level. Recent experiments in the
sponsor's laboratory demonstrated that rat cardiac muscle can be
transfected in vivo by the direct injection of plasmid DNA, and, further,
that the expression of an injected reporter gene coupled to a cellular
promoter is regulated in a tissue restricted and physiologically responsive
manner. These findings suggest a straightforward means with which to study
the regulation of cardiac genes in physiologic and pathologic states which
cannot be modeled in vitro. Hypertension induces the expression of the
beta-myosin heavy chain (MHC) gene in the ventricles of rats, in which the
alpha-MHC isoform predominates in the normotensive state. The goal of this
research project is to identify cis-acting elements responsive to
hypertension in the human beta-MHC gene and the nuclear proteins with which
these sequences interact. The specific aims are 1) to determine the
expression patterns of a reporter gene whose expression is driven by human
beta=MHC 5' flanking sequence following direct gene transfer into rat heart
in vivo; 2) to determine whether expression of this injected gene is
induced by renovascular hypertension; 3) to map hypertension responsive
elements in the 5' flanking sequence of the beta-MHC gene by direct
injection of constructs which hav been altered by mutagenesis; and 4) to
identify and to begin to purify and characterize nuclear proteins which
bind specifically with cis-acting hypertension responsive elements. These
studies are likely to provide an entry point from which to dissect the
signal transduction by which hypertension influences the expression of
specific cardiac genes.
StatusFinished
Effective start/end date7/1/926/30/93

Funding

  • National Heart, Lung, and Blood Institute

ASJC

  • Cardiology and Cardiovascular Medicine
  • Genetics
  • Molecular Biology
  • Physiology
  • Developmental Biology

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