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.

低钠血症是一种相对过量的身体水分，是最常见的电解质