Vascular smooth muscle cell (VSMC) populations undergo rearrangements from normal, contractile to pathological states in the course of diseases such as atherosclerosis and hypertension. It is self-evident that altered gene expression patterning not only accompanies this, but is intrinsic to the vascular remodeling process of disease. A picture has emerged in which genes typically associated with contractile function are down-regulated and replaced by those more supportive of a proliferative or pathological state. However, very little is known about mechanisms that regulate these shifts in VSMC gene expression patterns, or whether this represents an orchestrated process. Persistent or skewed exposure to a diverse array of extracellular factors, including growth factors, cytokines, lipids, hormones and neurotransmitters, have been implicated in VSMC dysfunction. This project will explore to what extent diverse extracellular signals may share common molecular mechanisms to down-regulate the expression of contractile- function genes in VSMC. The model system in this project is a microcosm of the vascular remodeling process. It involves cultured VSMC and an examination of the molecular mechanisms responsible for extracellular signal-induced destabilization of the mRNA encoding the angiotensin II AT1-receptor (AT1-R), serving as a prototypic contractile gene. That AT1-R mRNA is destabilized by representative growth factors, by hormones and cAMP-elevating agents, all in a translationally- and transcriptionally-coupled process, which suggests that a factor(s) is(are) induced to mediate this.
The aims of this study are: 1) to determine if a common signaling pathway integrates AT1-R mRNA decay induced by diverse classes of extracellular factors; 2) to establish the elements in the AT1-R mRNA molecule necessary for its destabilization in order to understand mechanisms for how specific mRNA's might be targeted by this destabilization process; 3) to determine to what extent AT1-R mRNA destabilizing signals alter translation of the mRNA and to establish the orle of AT1-R mRNA translation in its destabilization; 4) to isolate and clone documented AT1-R mRNA binding proteins induced by extracellular signals, as potential candidate factors involved in VSMC mRNA destabilization. State-of-the-art molecular genetic approaches will be exploited to manipulate VSMC gene expression.
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