Aging impairments in angiotensin type 1 receptor actions

血管紧张素1型受体作用的衰老损伤

基本信息

批准号：
8969870
负责人：
Kathryn L Sandberg
金额：
$ 23.33万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-15 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8969870
关键词：
Affect Age Aged, 80 and over Aging Agonist Alternative Splicing Alzheimer&apos s Disease Amino Acid Sequence Amino Acids Angiotensins Attenuated Blood Vessels Brain Cell Aging Cell Proliferation Chronic Code Consensus Sequence Diet Disease Electrolyte Balance Electrolytes Exons Fatty Liver Functional disorder Genes Genetic Transcription Goals Human Hypertension Immune Impairment Inbred F344 Rats Initiator Codon Inositol Kidney Knowledge Lead Mediating Messenger RNA Metabolic Metabolic Diseases Modeling Mood Disorders Mus Open Reading Frames Parkinson Disease Pathology Pathway interactions Peptides Phosphotransferases Physiological Play Proteins RNA RNA Interference RNA Splicing Rattus Receptor Signaling Receptor, Angiotensin, Type 1 Regulation Renin-Angiotensin System Role Sequence Homologs Signal Pathway Signal Transduction Smooth Muscle Myocytes Sodium Testing Transcript Transcriptional Regulation Translating Untranslated Regions Variant Vascular remodeling Water Water consumption age effect aged attenuation blood pressure regulation density extracellular interest mRNA Stability normal aging novel preference public health relevance receptor receptor binding receptor density receptor internalization receptor-mediated signaling tool urinary vascular smooth muscle cell proliferation

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this R21 proposal is to investigate the role of the PEP7 encoded short open reading frame in age-associated changes in AT1aR action in vascular smooth muscle cells. We will test the hypothesis that age-associated dysregulation of AT1aR densities contributes to vascular smooth muscle cell senescence in part through dysregulation of AT1aR splice variants, which leads to dysregulation of AT1aR internalization and signaling. To test this hypothesis, in Aim 1, we will determine the effect of aging on AT1aR transcript expression (E1,2,3 and E1,3), AT1R binding, rate of receptor internalization, AT1R signaling pathways and cell proliferation in vascular smooth muscle cells isolated from young (4 month old) and old (32 month old) Fischer rats. We will also use RNA interference to selectively inhibit expression of the E1,2,3-AT1aR transcript in vascular smooth muscle cells isolated from these young and old rats and determine the effect on AT1R binding, internalization, signaling and cell proliferation. In Aim 2, we will compare these same parameters in a disorder of vascular remodeling to investigate the role of PEP7 in normal and abnormal aging.

描述（由申请人提供）：该 R21 提案的总体目标是研究 PEP7 编码的短开放阅读框在血管平滑肌细胞中 AT1aR 作用的年龄相关变化中的作用，我们将检验年龄相关的假设。 AT1aR 密度失调部分通过 AT1aR 剪接变体失调导致血管平滑肌细胞衰老，从而导致 AT1aR 内化和信号传导失调。根据这一假设，在目标 1 中，我们将确定衰老对分离的血管平滑肌细胞中 AT1aR 转录表达（E1,2,3 和 E1,3）、AT1R 结合、受体内化速率、AT1R 信号通路和细胞增殖的影响我们还将使用 RNA 干扰选择性抑制从这些年轻大鼠中分离的血管平滑肌细胞中 E1,2,3-AT1aR 转录物的表达。在目标 2 中，我们将比较血管重塑疾病中的这些相同参数，以研究 PEP7 在正常和异常衰老中的作用。