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：
9120727
负责人：
Kathryn L Sandberg
金额：
$ 19.44万
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 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9120727
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 Disease Electrolyte Balance Electrolytes Exons Fatty Liver Functional disorder Genes Genetic Transcription Goals Health 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 Smooth Muscle Vascular remodeling Water Water consumption age effect aged attenuation blood pressure regulation density extracellular high salt diet interest mRNA Stability normal aging novel preference receptor receptor binding receptor density receptor internalization receptor-mediated signaling tool urinary vascular smooth muscle cell proliferation

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 Disease Electrolyte Balance Electrolytes Exons Fatty Liver Functional disorder Genes Genetic Transcription Goals Health 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 Smooth Muscle Vascular remodeling Water Water consumption age effect aged attenuation blood pressure regulation density extracellular high salt diet interest mRNA Stability normal aging novel preference receptor receptor binding receptor density receptor internalization receptor-mediated signaling tool urinary vascular smooth muscle cell proliferation

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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（由适用提供）：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与年龄相关的AT1AR作用变化中的作用。我们将检验以下假设：AT1AR密度与年龄相关的失调有助于通过AT1AR剪接变体失调，从而有助于部分血管平滑肌细胞感染，从而导致AT1AR内在化和信号传导失调。为了检验AIM 1，我们将确定衰老对AT1AR转录本表达（E1,2,3和E1,3）的影响，AT1R结合，受体内在化速率，AT1R信号传导途径和细胞在与年轻（4个月）和旧（32个月大的年龄）和老年（32个月大的年龄）中分离出的血管平滑肌细胞中的血管平滑肌细胞的增殖。我们还将使用RNA干扰来选择性地抑制从这些年轻大鼠和老鼠分离的血管平滑肌细胞中E1,2,3-AT1AR转录本的表达，并确定对AT1R结合，内在化，信号传导和细胞增殖的影响。在AIM 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。