MOLECULAR CONTROL--SMOOTH MUSCLE CALPONIN EXPRESSION

Project: Research project

Project Details

Description

The fully differentiated vascular smooth muscle cell (SMC) is endowed
with a genetic program of growth cessation and cell-restricted gene
expression, the encoded proteins of which coordinate the unique
contractile physiology of this muscle type. The functional role of one
such protein, smooth muscle calponin (SM-CALP), has received
considerable attention as an important modulator of SMC contraction and
cellular growth. Moreover, like many SMC differentiation genes, SM-CALP
expression is attenuated in vascular disease states (e.g.,
atherosclerosis), thus altering normal homeostasis within the vessel
wall. While its physiology has been studied extensively, little
information exists pertaining to the transcriptional control of SM-CALP.
Understanding the transcriptional regulation of SM-CALP will be of vital
importance in defining the basic molecular mechanisms that underlie both
normal SMC physiology and the altered function of these cells in disease
settings. Recently, a CArG box element residing in the 5' promoter of
several SMC-restricted genes has been implicated in SMC-specific gene
expression. However, transgenic studies point to more complex modes of
muscle gene regulation that include the participation of regulatory
elements residing great distances from the core promoter sequence. This
application will test the thesis that SM-CALP expression multiple
regulatory elements, including those far removed from the core promoter,
that are functionally inactivated in the context of vascular disease.
Proposed studies will examine the potential role of an intronic CArG box
on SM-CALP promoter activity using cells and transgenic mice. Further
studies will use innovative "genome tools" to identify regulatory
elements that may reside long distances from the core promoter. Such
elements will then be tested in an in vivo model of vascular stenosis
using an adenoviral-mediated reporter gene transfer method. These
studies will contribute significantly to our understanding of the
transcriptional control of SM-CALP during normal development and
diseases, especially those of the vasculature. Such information will
facilitate the design and implementation of potentially novel molecular
interventions for the treatment of vascular disease.
StatusNot started