Novel mechanisms of HDAC1 regulation of renal collecting duct function

描述(由申请人提供)：水平衡是通过血管加压素(AVP)调节的水通道-2(AQP2)调节肾集合管(CD)对水的重吸收来维持的。AQP2的功能障碍会导致肾源性尿崩症(多尿)或抗利尿综合征(水分滞留)等疾病，严重的液体滞留是心血管疾病的常见疾病。组蛋白脱乙酰基酶(HDACs)去除组蛋白赖氨酸上的乙酰基，导致基因转录或非组蛋白蛋白翻译后的表观遗传修饰。由于HDAC抑制剂的抗炎作用，人们对其在心血管疾病中的治疗应用越来越感兴趣。有趣的是，据报道，使用HDAC抑制剂的一个副作用是低钠血症，这表明这些药物影响液体平衡。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中蛋白质的转录和去乙酰化来调节利尿的新作用。我们的中心假设是，在过量的水分消耗中，HDAC1通过直接去乙酰化AQP2来调节AQP2的表达，间接地通过减少AVP亚型2受体(V2R)的表达来调节AQP2的表达，并间接地通过增加一氧化氮合酶-1(NOS1)衍生的一氧化氮(NO)来调节利尿。将检验以下假设：1)检验通过集合导管AQP2乙酰化和心尖表面表达的变化来维持水平衡的假设；2)检验水合作用促进CD中AQP2去乙酰化和/或通过HDAC1下调V2R受体从而促进利尿的假设；3)检验依赖HDAC1的CD NO增加导致AQP2表面表达减少的假设。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，即在心脏/肾脏生理学领域开发一个强大的、独立的研究计划，专注于解决心脏/肾脏疾病潜在的新机制。

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.