Lysine Acetylation and the Regulation of Vasopressin/Aquaporin System in the Principal Cell

主细胞中赖氨酸乙酰化和加压素/水通道蛋白系统的调节

基本信息

批准号：
10662292
负责人：
Kelly Hyndman
金额：
$ 22.28万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-06 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10662292
关键词：
ATAC-seq Acetylation Acetyltransferase Acute Agonist Animal Experiments Animals Area Argipressin Cell Culture Techniques Cell Nucleus Cells ChIP-seq Chromatin Structure Chronic Clinical Complement Coupled Cytosol Data Deacetylase Deacetylation Dehydration Duct (organ) structure Ductal Epithelial Cell Electrolyte Balance Electrolyte Disorder Electrolytes Enzymes Epigenetic Process FDA approved Fluid Balance Gene Expression Genetic Genetic Transcription Glycerol HDAC1 gene HDAC2 gene Half-Life Hematopoietic Neoplasms Histone Acetylation Histone Deacetylase Histone Deacetylase Inhibitor Histone Deacetylation Histones Human Hydration status Hydrogen Peroxide Hyponatremia In Vitro Kidney Liquid substance Lysine Measures Mediating Meta-Analysis Methylation Modification Mus Mutant Strains Mice Mutation Odds Ratio Oocytes Pathway interactions Permeability Phosphorylation Physiological Plasma Polyuria Post-Translational Protein Processing Proteins Publishing Rana Rattus Regulation Reporting Research Sodium System Systems Biology Testing Transcriptional Regulation Urea Urine Vasopressin Receptor Vasopressins Water Water-Electrolyte Balance absorption apical membrane aquaporin 3 argipressin receptor basolateral membrane cancer therapy clinically significant epigenetic drug epigenetic regulation equilibration disorder experience experimental study gene network in vivo interstitial kidney cell kidney medulla mimetics non-histone protein novel novel therapeutics prevent protein function single nucleus RNA-sequencing trafficking transcriptome urinary water channel water conservation

项目摘要

SUMMARY Dysregulation of arginine vasopressin (AVP) and water channels, called aquaporins (AQPs), can lead to a variety of clinically-significant water-electrolyte problems, ranging from severe dehydration to low plasma sodium. The actions of AVP in the kidney are mediated via the AVP receptor 2 (AVPR2) predominantly on the kidney principal cell. The AVP-sensitive water channels, AQP2 and AQP3, promote water reabsorption to prevent dehydration. In doing so these water channels function to concentrate the urine. Based on our compelling preliminary data, this proposal focuses on the first reported modification of AQP3, lysine 282 acetylation, in the regulation of substrate permeability. Lysine acetylation is also important for gene expression and it is regulated via acetyltransferases and deacetylases (HDACs) enzymes. We recently performed a systemic review and metanalysis and determined that chronic HDAC inhibitor use, as occurs in the treatment of cancers, results in a significant >2 odds ratio of experiencing fluid-electrolyte disorders in humans. Thus, determining the functional significance of lysine acetylation in the kidney is critically important both from a physiological perspective and in understanding the clinical impact of HDAC inhibition on water-electrolyte balance. Together, our compelling preliminary data have led us to formulate the overarching hypothesis that regulation of the kidney AVPR2/AQP axis by lysine acetylation is critical in regulating urinary concentrating ability and fluid balance. This will be tested by the following two aims: Aim 1: To test the hypothesis that lysine acetylation of AQP3 increases substrate flux in the principal cell promoting urine concentration. Aim 2: To test the hypothesis that HDAC1 and HDAC2 regulate the transcription of the AVPR2/AQP axis in the principal cell. We will combine unbiased, system biology approaches with cell to whole animal experiments to close key gaps in our understanding of concentrating mechanisms in the kidney and may reveal new therapeutic avenues to treat fluid-electrolyte disorders.

概括精氨酸加压素 (AVP) 和水通道（称为水通道蛋白 (AQP)）的失调可导致多种疾病临床上显着的水电解质问题，从严重脱水到低血浆钠。这 AVP 在肾脏中的作用主要是通过 AVP 受体 2 (AVPR2) 介导的细胞。 AVP 敏感的水通道 AQP2 和 AQP3 可促进水的重吸收以防止脱水。在此过程中，这些水通道的作用是浓缩尿液。根据我们令人信服的初步数据，该提案重点关注首次报道的 AQP3 赖氨酸 282 乙酰化修饰，在调节基材渗透性。赖氨酸乙酰化对于基因表达也很重要，它是通过以下途径调节的：乙酰转移酶和脱乙酰酶 (HDAC)。我们最近进行了系统审查荟萃分析并确定长期使用 HDAC 抑制剂（如癌症治疗中发生的情况）会导致人类经历液体电解质紊乱的显着>2 优势比。因此，确定函数赖氨酸乙酰化在肾脏中的重要性无论从生理角度还是在了解 HDAC 抑制对水电解质平衡的临床影响。在一起，我们引人注目初步数据使我们得出总体假设：肾脏 AVPR2/AQP 的调节赖氨酸乙酰化作用的轴对于调节尿液浓缩能力和体液平衡至关重要。这将被测试通过以下两个目标：目标 1：检验 AQP3 的赖氨酸乙酰化增加底物通量的假设在主细胞中促进尿液浓缩。目标 2：检验 HDAC1 和 HDAC2 的假设调节主细胞中 AVPR2/AQP 轴的转录。我们将结合公正的系统生物学从细胞到整个动物实验的方法来缩小我们对集中注意力理解的关键差距肾脏机制，并可能揭示治疗液体电解质紊乱的新治疗途径。