Angiotensin Receptor Regulation By Upstream Short Open Reading Frames

上游短开放阅读框对血管紧张素受体的调节

基本信息

批准号：
9005356
负责人：
Willis K. Samson
金额：
$ 10.67万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-17 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9005356
关键词：
Address Adrenal Glands Affect Age Aging Aging-Related Process Alzheimer&apos s Disease Amino Acid Sequence Amino Acids Angiotensin II Angiotensin Receptor Angiotensin Type 1a Receptor Angiotensins Animals Anxiety Attenuated Blood Pressure Blood Vessels Brain Cardiovascular Physiology Cardiovascular system Cells Characteristics Chronic Kidney Failure Code Consensus Sequence Defect Diet Disease Electrolyte Balance Electrolytes Equilibrium Exons Fatty Liver Functional disorder Funding Funding Mechanisms Goals Grant Health Homeostasis Human Hypertension Hypotension Immune Impairment Inbred F344 Rats Individual Initiator Codon Inositol Intake Kidney Concentrating Ability Lead Liquid substance Maintenance Mediating Mental Depression Messenger RNA Metabolic Diseases Metabolic syndrome Mitogen-Activated Protein Kinases Modeling Mood Disorders Multiple Sclerosis Mus Neuraxis Non-Insulin-Dependent Diabetes Mellitus Open Reading Frames Parkinson Disease Pathology Peptides Phenotype Physiological Play Predisposition Production Protein Kinase Proteins RNA Splicing Rattus Receptor Gene Receptor Signaling Receptor, Angiotensin, Type 1 Regulation Renin-Angiotensin System Reporting Resistance Role Sequence Analysis Signal Transduction Sodium Stroke Supplementation Testing Therapeutic Thirst Tissues Transcript Translating Variant Water age related aged blood pressure reduction blood pressure regulation density drinking water environmental change extracellular in vivo interest juvenile animal normal aging novel novel therapeutic intervention receptor receptor binding receptor expression receptor function response trafficking urinary

项目摘要

DESCRIPTION (provided by applicant):Angiotensin II (Ang II) plays a key role in fluid homeostasis and blood pressure (BP). We recently found that a seven amino acid peptide (PEP7) encoded within a short open reading frame in exon 2 of the 5' leader sequence of the angiotensin type 1a receptor (AT1aR) mRNA inhibits Ang II activation of extracellular signal-regulated protein kinases 1 and 2 (Erk1/2) and regulates AT1aR trafficking in cells. PEP7 also markedly reduced Ang II-mediated sodium intake without having any effect on Ang II-mediated water drinking and it antagonized Ang II-induced increases in BP. Recognizing that with aging come significant changes in thirst, urinary concentrating ability and the ability to excrete water and electrolytes, we determined if aging alters the ratio of expression of the two splice variants of the AT1aR [one that encodes PEP7 (E-1,2,3-AT1aR) and the other that does not (E-1,3-AT1aR)] and found, indeed, that young animals express a higher ratio of E-1,2,3-AT1aR/E-1,3-AT1aR than aged animals. We also observed that aging affects the density of AT1R binding in adrenal gland. Thus changes in the expression of PEP7 (present in higher levels in young compared to older animals because of changes changes in E-1,2,3- and E-1,3-AT1aR expression) may lead to impaired AT1R regulation in response to environmental changes in electrolyte balance. Studies proposed in this application (supplement to our funded grant HL121456) address the hypothesis that the ratio of the expression of the splice variants of the AT1aR changes with aging, favoring the E-1,3-AT1aR, resulting in less PEP7 production, and contributing to age-associated impairments in fluid and electrolyte homeostasis and blood pressure. We will determine if supplementation with PEP7 in aged animals returns their fluid homeostasis to normal and if reduction in PEP7 production in young animals precipitates the aged phenotype. Renin-angiotensin system dysfunction is associated with diverse pathologies associated with aging. Therefore, these studies may lead to novel therapeutic approaches for the treatment of age-related alterations in fluid homeostasis and cardiovascular function.

描述（由适用提供）：ANG II（ANG II）在流体体内平衡和血压（BP）中起关键作用。我们最近发现，在5'领导者2型1A型受体（AT1AR）mRNA的5'领导者2序列中编码的七个氨基酸肽（PEP7）抑制了ANG II激活细胞外信号调节的蛋白质激活蛋白1和2（ERK1/2），并在1AR pep7中均在1AR中进行了调节。 II介导的水饮用并拮抗ANG II诱导的BP的增加。认识到，随着年龄的重大变化，尿液浓缩能力和准确水和电解质的能力发生了重大变化，我们确定衰老是否改变了AT1AR的两个剪接变体的表达之比[一个编码PEP7（E-1,2,3-AT1AR），而另一个人则没有（E-1,3-AT1AR），并在较高（E-1,3-AT1AR）和其他情况下，确实如此。 E-1,2,3-AT1AR/E-1,3-AT1AR比老年动物。我们还观察到衰老会影响肾上腺中AT1R结合的密度。 PEP7表达的变化（由于E-1,2,3-和E-1,3-AT1AR表达的变化变化，与老年动物相比，年轻动物的水平较高，可能会导致AT1R调节受损，以应对电解质平衡的环境变化。在本申请中提出的研究（补充了我们资助的Grant HL121456）解决了以下假设：AT1AR的剪接变体的表达之比与衰老变化，有利于E-1,3-AT1AR的E-1,3-AT1AR，导致PEP7的产生较少，导致年龄相关的液体和电解质构型和血液中的损害。我们将确定在老年动物中补充PEP7是否会使它们的液体体内稳态恢复正常，以及年轻动物中PEP7产生的降低是否可以保留老化的表型。肾素 - 血管紧张素系统功能障碍与与衰老相关的潜水病理学有关。因此，这些研究可能导致新型的治疗方法，用于治疗与年龄相关的液体稳态和心血管功能的改变。