A Novel Locus in the Regulation of Human Water Balance

低钠血症，相对过剩的总身体水分，是最常见的电解质 异常虽然有些情况很容易归因于心脏，肝脏或肾脏衰竭，但许多情况下， 无法解释水分过多会导致意识模糊、嗜睡、癫痫发作和死亡。甚至轻度低钠血症 会导致协调和认知的可逆性缺陷。 申请人的初步数据表明，血浆钠浓度具有高度个体性（即， 在任何一个个体中相对恒定）并且是可遗传的。在一项针对以下疾病的全基因组关联研究中， 影响水平衡的常见基因变异，申请人及其同事在 一种以前没有被怀疑在全身水分平衡中发挥作用的基因，但表现出极强的 生物相容性高。前导变体影响基因内的内含子增强子。值得注意的是， 第二个关联基因座编码预测与该增强子结合的转录因子。因此，我们认为， 这个建议的首要目标是证明这个增强子区域的中心地位， 基因变体，并使用体外和全基因组的组合将该基因用于系统性调节。 动物模型 在目标1中，功能意义（即，增强子区域和等位基因的渗透反应性）- 将通过报告基因和DNA结合分析来探测特定的作用。在目标2中， 在渗透表型后下调该基因将在天然表达 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，以及对设计的生理操作的响应 扰乱水平衡

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.