A Novel Locus in the Regulation of Human Water Balance

人体水平衡调节的新途径

• 批准号: 10047697
• 负责人: DAVID M COHEN
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-10-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10047697
• 关键词: Address; Affect; Affinity; Algorithms; Alleles; Animal Model; Animals; Binding; Biological; Biological Assay; Blood Chemical Analysis; Body Water; Brain; Cell Culture Techniques; Cell Line; Cell Volumes; Cells; Cerebral Edema; Cessation of life; Clinical; Code; Cognition; Coma; Confusion; Consensus; Cultured Cells; DNA; DNA Binding; Data; Disease; Electrolytes; Elements; Engineering; Enhancers; Equilibrium; Excretory function; Exhibits; Family; Gene Expression; Genes; Genetic; Heart failure; Heritability; Human; Hyponatremia; Impairment; In Vitro; Inappropriate ADH Syndrome; Individual; Inherited; International; Introns; Investigation; Islets of Langerhans; Kidney Failure; Knock-out; Lead; Lethargies; Liver Failure; Location; Measures; Minor; Modeling; Molecular; Mus; Mutation; Osmolalities; Osmoregulation; Patients; Phenotype; Physiological; Plasma; Play; Population; Population Genetics; Predictive Factor; Predisposing Factor; Proteins; Quantitative Trait Loci; Regulation; Reporter Genes; Risk; Role; Seizures; Series; Signal Transduction; Site; Sodium; Sodium Bicarbonate; Sodium-Bicarbonate Symporters; Stress; Syndrome; Testing; Tissues; Transgenic Mice; Tube; United States Department of Veterans Affairs; Variant; Water; antidiuresis; base; cohort; design; gene product; genetic variant; genome wide association study; member; metagenome; mouse model; novel; programs; response; sensor; solute; trait; transcription factor

Hyponatremia, a relative excess of total body water, is the most frequently encountered electrolyte abnormality. Although some instances are readily attributed to heart, liver, or kidney failure, many are unexplained. Water excess causes confusion, lethargy, seizures, and death. Even mild hyponatremia causes reversible deficits in coordination and cognition. The applicant's preliminary data show that the plasma sodium concentration is highly individual (i.e., relatively constant in any one individual) and is heritable. In a meta-genome-wide association study for common gene variants that influence water balance, the applicant and co-workers identified variants in a gene not previously suspected of playing a role in whole-body water balance, but exhibiting extremely high biological plausibility. The lead variant affects an intronic enhancer within the gene. Remarkably, a second association locus codes for the transcription factor predicted to bind this enhancer. Therefore, the overarching objective of this proposal is to demonstrate the centrality of this enhancer region, this gene variant, and this gene to systemic osmoregulation using a combination of in vitro and whole- animal models. In Aim 1, the functional significance (i.e., osmotic responsiveness) of the enhancer region and allele- specific effects will be probed through reporter gene and DNA binding assays. In Aim 2, the effect of downregulating this gene upon osmotic phenotype will be tested in cultured cells natively expressing the protein. In Aim 3, transgenic mouse models will be used to test the importance of this gene to systemic water balance under basal conditions, and in response to physiological maneuvers designed to perturb water balance.

低钠血症是指体内水分相对过量，是最常见的电解质 紊乱 etc。尽管有些情况很容易归因于心脏、肝脏或肾衰竭，但许多情况是 无法解释。水分过多会导致精神错乱、嗜睡、癫痫发作和死亡。即使是轻度低钠血症 导致协调和认知方面的可逆性缺陷。 申请人的初步数据显示，血浆钠浓度具有高度个体化性（即， 在任何一个个体中都相对恒定）并且是可遗传的。在一项全基因组关联研究中 影响水平衡的常见基因变异，申请人和同事发现了变异 以前并未怀疑该基因在全身水平衡中发挥作用，但表现出极其 高生物学合理性。先导变异影响基因内的内含子增强子。值得注意的是，一个 第二个关联基因座编码预测结合该增强子的转录因子。所以， 该提案的总体目标是证明该增强子区域的中心地位 基因变体，并且该基因使用体外和整体的组合来进行全身渗透调节 动物模型。 在目标 1 中，增强子区域和等位基因的功能意义（即渗透反应性） 具体效果将通过报告基因和 DNA 结合测定来探测。在目标 2 中，效果 将在天然表达的培养细胞中测试根据渗透表型下调该基因 蛋白质。在目标 3 中，将使用转基因小鼠模型来测试该基因对 基础条件下的全身水平衡，以及响应设计的生理操作 扰乱水平衡。