A Novel Locus in the Regulation of Human Water Balance

人体水平衡调节的新途径

• 批准号: 10474258
• 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/10474258
• 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.

低钠血症是总体水的相对过量，是最常遇到的电解质 紊乱 etc。尽管某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。多余的水会导致混乱，嗜睡，癫痫发作和死亡。甚至轻度低钠血症 导致协调和认知的可逆缺陷。 申请人的初步数据表明，血浆钠浓度是高度个性的（即 任何一个人都相对稳定），是可遗传的。在一项元基因组范围的关联研究中 影响水平平衡的常见基因变异，申请人和同事确定了变体 以前不怀疑的基因在全身水平上发挥作用，但表现出极端的表现 高生物学合理性。铅变体会影响基因内的内含子增强子。值得注意的是， 第二个关联基因座代码用于结合该增强子的转录因子。所以， 该提议的总体目的是证明该增强子地区的中心地位，这 基因变体，以及该基因对全身性渗透调节的基因，结合了体外和全体 动物模型。 在AIM 1中，增强子区域和等位基因的功能意义（即渗透反应能力） 特定效应将通过报告基因和DNA结合测定进行探测。在AIM 2中，效果 在渗透表型上下调该基因将在培养的细胞中测试 蛋白质。在AIM 3中，转基因小鼠模型将用于测试该基因对 在基础条件下的全身水平 扰动水平衡。

项目成果

Heritability and individuality of the plasma sodium concentration: a twin study in the United States veteran population.

血浆钠浓度的遗传性和个体性：美国退伍军人群体的一项双胞胎研究。

• DOI: 10.1152/ajprenal.00581.2018
• 发表时间: 2019
• 期刊: American journal of physiology. Renal physiology
• 作者: Timmons,AndrewK;Korpak,AnnaM;Tan,Jenny;Moore,KathrynP;Liu,CindyH;Forsberg,ChristopherW;Goldberg,Jack;Smith,NicholasL;Cohen,DavidM
• 通讯作者: Cohen,DavidM