Human Angiotensin II Receptor Gene Regulation

人血管紧张素 II 受体基因调控

• 批准号: 6436185
• 负责人: TERRY S ELTON
• 金额: $ 21.9万
• 依托单位: BRIGHAM YOUNG UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-08-01 至 2005-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6436185
• 关键词: RNA splicing; affinity chromatography; angiotensin II; angiotensin receptor; cell line; fluorescence resonance energy transfer; genetic regulation; genetic transcription; genetic translation; messenger RNA; polymerase chain reaction; protein isoforms; receptor expression; ribosomes; transcription factor; transfection; vascular smooth muscle

Abnormal growth of vascular smooth muscle cells (VSMC) is central to the pathophysiology of various cardiovascular diseases such as atherosclerosis, hypertension and restenosis after angioplasty. These abnormalities can be manifested as changes in the state of VSMC proliferation, differentiation, gene expression patterns and morphology. Currently, the peptide hormone, angiotensin II (Ang II), is believed to play a pivotal role in the development of hypertension and atherosclerosis since it acts as a growth promoting factor in VSMC. The biological responses to Ang II are mediated by its interaction with two distinct high affinity G protein-coupled receptors (GPCRs) now designated AT1R and AT2R. While characterizing the human AT1R (hAT1R) gene, it was demonstrated that human tissues can express at least eight alternatively spliced hAT1R mRNA transcripts which differ only in their 5'-untranslated regions (5'-UTR). Currently, very little is known about the functional significance of each splice variant or how they are regulated. Therefore, the long term goals of this project are to functionally characterize each splice variant and to investigate the molecular mechanisms that govern the expression of these mRNAs. An understanding of these processes is critical since aberrant transcriptional, post- transcriptional and/or translational regulation of hAT1R gene expression may result in the over-expression of the hAT1R which would lead to exaggerated Ang II responsiveness and possibly result in cardiovascular disease. The Specific Aims of this proposal are to: 1) Test the hypothesis that hAT1R mRNA splice variants are differentially expressed in human tissues and investigate the transcriptional regulation of the hAT1R gene by the distal and proximal promoter regions, 2) Test the hypothesis that hAT1R mRNA splice variants have distinct mRNA half-lives, which can be regulated by physiological stimuli, 3) Test the hypothesis that hAT1R mRNA splice variants are translated with different efficiencies, 4) Characterize the internal ribosome entry site (IRES) harbored in exon-1 of the hAT1R mRNA 5'-UTR and identify trans-acting factors which recognize this element, and 5) Test the hypothesis that "long" and "short" hAT1R isoforms can form hetero-dimers and that these hetero-dimers are functionally distinct.

血管平滑肌细胞（VSMC）的异常生长对于各种心血管疾病（例如动脉粥样硬化，高血压和血管成形症）等各种心血管疾病的病理生物学至关重要。 这些异常可以表现为VSMC增殖状态，分化，基因表达模式和形态的变化。 目前，据信肽激素激素II（ANG II）在高血压和动脉粥样硬化的发展中起关键作用，因为它是促进VSMC的生长因素。 对ANG II的生物反应是通过与现在指定为AT1R和AT2R的两个不同高亲和力G蛋白偶联受体（GPCR）的相互作用介导的。 在表征人AT1R（HAT1R）基因的同时，证明了人体组织至少可以表达八个剪接的HAT1R mRNA转录本，这些转录仅在其5'-非翻译区域（5'-utr）中有所不同。当前，对于每个剪接变体的功能重要性或它们的调节方式知之甚少。 因此，该项目的长期目标是在功能上表征每个剪接变体，并研究控制这些mRNA表达的分子机制。 对这些过程的理解至关重要，因为对HAT1R基因表达的异常转录，转录后和/或翻译调节可能会导致HAT1R的过表达，这会导致ANG ANG II的反应性夸大，并可能导致心血管疾病。 The Specific Aims of this proposal are to: 1) Test the hypothesis that hAT1R mRNA splice variants are differentially expressed in human tissues and investigate the transcriptional regulation of the hAT1R gene by the distal and proximal promoter regions, 2) Test the hypothesis that hAT1R mRNA splice variants have distinct mRNA half-lives, which can be regulated by physiological stimuli, 3) Test the hypothesis that hAT1R mRNA splice variants are translated with different efficiencies, 4) Characterize the internal ribosome entry site (IRES) harbored in exon-1 of the hAT1R mRNA 5'-UTR and identify trans-acting factors which recognize this element, and 5) Test the hypothesis that "long" and "short" hAT1R isoforms can form hetero-dimers and that these hetero-dimers are functionally distinct.