Novel mechanisms of HDAC1 regulation of renal collecting duct function

HDAC1调节肾集合管功能的新机制

基本信息

批准号：
8868322
负责人：
Kelly Hyndman
金额：
$ 15.19万
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：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8868322
关键词：
AVPR2 gene Acetylation Acute Address Adverse effects Advisory Committees Affect Anti-Inflammatory Agents Anti-inflammatory Apical Body Fluids Body Water Brattleboro Rats Cardiovascular Diseases Cells Chronic Complication Data Deacetylation Dehydration Development Diet Disease Diuresis Down-Regulation Duct (organ) structure Electrolytes Enzymes Epigenetic Process Equilibrium Excretory function Figs - dietary Fluid Balance Functional disorder Genetic Transcription Goals HDAC1 gene Health Histone Deacetylase Histones Homeostasis Hydration status Hyponatremia In Vitro Inappropriate ADH Syndrome Infusion procedures Kidney Kidney Concentrating Ability Kidney Diseases Knockout Mice Link Liquid substance Lysine Mass Spectrum Analysis Mediating Mediator of activation protein Mentors Modeling Modification Mus Nephrogenic Diabetes Insipidus Nitric Oxide Nitric Oxide Synthase Type I Non-Histone Chromosomal Proteins Pathway interactions Pharmaceutical Preparations Phosphorylation Physiological Processes Physiology Polyuria Post-Translational Regulation Production Property Proteins Rattus Regulation Regulatory Pathway Reporting Research Risk Factors Role Signal Transduction Site Small Interfering RNA Sodium Chloride Surface Syndrome Testing Therapeutic Uses Transcriptional Regulation Vasopressins Water Water consumption antidiuresis apical membrane aquaporin-2 in vivo inhibitor/antagonist interest interstitial novel programs protein function receptor research study trafficking water channel

项目摘要

DESCRIPTION (provided by applicant): Water balance is maintained through the regulation of water reabsorption by the renal collecting duct (CD) via the vasopressin (AVP) regulated water channel aquaporin-2 (AQP2). Dysfunction in AQP2 leads to diseases such as nephrogenic diabetes insipidus (polyuria) or antidiuresis syndrome (water retention), and severe fluid retention is a common ailment in cardiovascular disease. Histone deacetylase enzymes (HDACs) remove acetyl groups from lysines of histones leading to epigenetic modification of gene transcription or non-histone proteins in a post-translational manner. There is growing interest in the therapeutic use of HDAC inhibitors in cardiovascular disease because of their anti- inflammatory properties. Interestingly, a reported side effect of HDAC inhibitor use is hyponatremia, suggesting these drugs affect fluid balance. Thus, it is imperative that we gain a better understanding of the role of HDACs in body fluid balance in order to avoid potentially dangerous side effects. Our compelling preliminary data support a novel role for HDAC1 regulation of diuresis by regulating transcription and deacetylation of proteins in the CD. Our central hypothesis is that during excess water consumption, HDAC1 mediates diuresis via regulation of AQP2 apical expression by directly deacetylating AQP2, indirectly by decreasing expression of the AVP subtype 2 receptor (V2R), and indirectly by increasing in nitric oxide synthase-1 (NOS1) derived nitric oxide (NO). The following hypotheses will be tested: 1) To test the hypothesis that water balance is maintained by changes in collecting duct AQP2 acetylation and apical surface expression; 2) To test the hypothesis that hydration promotes deacetylation of AQP2 and/or downregulation of the V2R receptor via HDAC1 in the CD, thus promoting diuresis; 3) To test the hypothesis that HDAC1-dependent increases in CD NO derived from NOS1 leads to decreases in AQP2 surface expression. With the help of mentor and advisory team, I will continue on the path towards my long term goal of developing a strong, independent, research program in the field of cardio/renal physiology with a focus on addressing novel mechanisms underlying cardio/renal diseases.

描述（由申请人提供）：水平衡是通过肾集合管（CD）通过加压素（AVP）调节的水通道水通道蛋白-2（AQP2）调节水重吸收来维持的。 AQP2 功能障碍会导致肾性尿崩症（多尿）或抗利尿综合征（水潴留）等疾病，而严重的液体潴留是心血管疾病的常见疾病。组蛋白脱乙酰酶 (HDAC) 可去除组蛋白赖氨酸中的乙酰基，从而以翻译后方式对基因转录或非组蛋白进行表观遗传修饰。由于 HDAC 抑制剂的抗炎特性，人们对 HDAC 抑制剂在心血管疾病中的治疗用途越来越感兴趣。有趣的是，据报道，使用 HDAC 抑制剂的副作用是低钠血症，表明这些药物会影响体液平衡。因此，我们必须更好地了解 HDAC 在体液平衡中的作用，以避免潜在的危险副作用。我们令人信服的初步数据支持 HDAC1 通过调节 CD 中蛋白质的转录和脱乙酰化来调节利尿的新作用。我们的中心假设是，在过量饮水期间，HDAC1 通过直接使 AQP2 去乙酰化、间接通过降低 AVP 亚型 2 受体 (V2R) 的表达以及间接通过增加一氧化氮合酶 1 (NOS1) 来调节 AQP2 顶端表达，从而介导利尿。）衍生一氧化氮（NO）。将测试以下假设： 1）测试通过集合管 AQP2 乙酰化和顶端表面表达的变化来维持水平衡的假设； 2) 检验水合促进 CD 中 AQP2 脱乙酰化和/或通过 HDAC1 下调 V2R 受体，从而促进利尿的假设； 3) 检验以下假设：NOS1 衍生的 CD NO 的 HDAC1 依赖性增加导致 AQP2 表面表达减少。在导师和顾问团队的帮助下，我将继续朝着我的长期目标前进，即在心/肾生理学领域开发一个强大的、独立的研究项目，重点是解决心/肾疾病的新机制。