REGULATION OF VASCULAR SMOOTH MUSCLE MRNA STABILITY

血管平滑肌 mRNA 稳定性的调节

• 批准号: 2839030
• 负责人: Thomas J. Murphy
• 金额: $ 19.78万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-01 至 2001-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2839030
• 关键词: RNA binding protein; angiotensin receptor; angiotensins; bacteriophage lambda; biological signal transduction; chemical stability; gene expression; genetic techniques; genetic translation; isoproterenol; messenger RNA; molecular cloning; muscle contraction; northern blottings; nucleic acid structure; protein biosynthesis; protein kinase A; receptor expression; site directed mutagenesis; transcription factor; vascular smooth muscle; western blottings; yeasts

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.

血管平滑肌细胞（VSMC）群体经历重排