Polymorphism affecting water balance
多态性影响水平衡
基本信息
- 批准号:8262628
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-07-01 至 2014-06-30
- 项目状态:已结题
- 来源:
- 关键词:AccountingAcidsAddressAdverse effectsAffectAllelesAmino AcidsAnimal ModelAnimalsAntidepressive AgentsAntipsychotic AgentsBackBiological AssayBlood Chemical AnalysisBody WaterCationsCaucasiansCaucasoid RaceChronicChronically IllClinicalCodeCognitionComplexControlled StudyDNADataData SetDiseaseDiureticsElderlyElectrolytesEquilibriumEthnic OriginExcretory functionExhibitsExonsFamilyGenesGeneticGenetic MarkersGenetic PolymorphismGenomicsGenotypeGerm LinesHaplotypesHeartHeredityHumanHypernatremiaHyponatremiaHypothalamic structureIn VitroIndividualIndividual DifferencesInjection of therapeutic agentInterventionIntronsInvestigationIon ChannelKnock-in MouseLifeLinkLinkage DisequilibriumMediatingMediator of activation proteinMedicalMetabolismMinorityModelingMusMutationNot Hispanic or LatinoOrganismOsmoregulationPatientsPharmaceutical PreparationsPhasePhenotypePhysiologicalPopulationPopulation StudyPredisposing FactorPredispositionPrevalenceProcessPropertyProteinsRNA SplicingRegulationRegulator GenesReporter GenesRiskRoleSeriesSerumSeveritiesSignal TransductionSingle Nucleotide PolymorphismSodiumSpliced GenesStressSystemTestingTransgenic OrganismsTubeVariantVeteransWaterWater consumptionWild Type Mouseanaloganimal dataarachidonatebaseblastocystcase-basedcohortcollecting tubule structuredesignembryonic stem cellfallsgenetic regulatory proteinhomologous recombinationhuman datahuman subjectin vitro testingin vivoindexinglipid mediatormembermouse modeloutcome forecastpromoterreceptorrecombinaseresponsesensortransmission processvector
项目摘要
DESCRIPTION (provided by applicant):
Disorders of water balance (i.e., hypernatremia and hyponatremia) are the most frequently encountered of the electrolyte problems; they are exceedingly common among the elderly, the acutely and chronically ill, and among patients taking certain diuretic and anti-depressant medications. All of these predisposing factors are present in a high percentage of patients served by the Department of Veterans Affairs. Aberrant water balance further complicates many chronic medical conditions and confers a poor prognosis independent of the severity of the underlying illness. Recent data from well-controlled studies indicate that even subtle abnormalities in systemic water balance can seriously affect coordination and cognition, and the propensity to falls. Regulation of body water balance is a complex process coordinated by the hypothalamus and executed by the kidney collecting duct; however, the central sensors of systemic tonicity had remained obscure. Recently, members of the transient receptor potential family of cation channels were proposed to serve this role, based upon extensive in vitro data and animal studies. We reasoned that a common single- nucleotide polymorphism in one of these genes may account for individual differences in systemic water balance among healthy elderly human subjects. We identified one such polymorphism in a key water- regulatory gene that confers an amino acid change and results in a protein with aberrant function in vitro. Importantly, we found that the presence of this polymorphism is strongly associated with hyponatremia in two healthy human populations. Furthermore, the effect size is large: the risk of hyponatremia is more than doubled by the presence of a single copy of this allele. To cement this relationship, we propose three experimental aims. In Aim I, we will sequence the haplotype block in which this polymorphism is embedded, to establish that no other polymorphism in tight linkage disequilibrium with our known variant accounts for the effect of this allele. Although we strongly suspect that this is the case, based upon our sequencing of all coding exons and splice junctions in this block, a robust conclusion requires phasing the entire haplotype block. This will also aid our investigation of multiple ethnicities. In Aim II, we will test additional large human populations for the presence of this polymorphism to confirm its association with serum sodium concentration and with hyponatremia. In Aim III, we will test for the role of epoxyeicosatrienoic acid signaling in systemic water balance in normal mice. Second, we will "knock in" the variant allele of the water-regulatory gene in a mouse model to test if it can independently recapitulate the human hyponatremic phenotype. We further propose to apply a number of physiological maneuvers to unmask a latent water-retentive phenotype. There is extremely high conservation between the human and mouse gene, including the amino acid affected by this polymorphism and its immediate context. Of note, we will not create a transgenic harboring an "extra" allele with this polymorphism; we will replace one or both wild-type alleles with a murine analog of this variant allele. In addition, in this Aim we will test the role of the epoxyeicosatrienoic acid system in regulating systemic water balance, in both wild-type and knock-in mice. There are no data addressing the role of this system in water balance in vivo, although it mediates tonicity-sensing by central osmosensing channels and we now show in our preliminary data that this effect is interrupted by our key polymorphism.
PUBLIC HEALTH RELEVANCE:
Disorders of water balance are among the most frequently encountered and morbid of the blood chemistry problems; they are exceedingly common among the elderly, the acutely and chronically ill, and among patients taking certain diuretic and anti-depressant medications. All of these predisposing factors are present in a high percentage of patients served by the Department of Veterans Affairs. We show that a common genetic change in a key water-regulatory protein increases the risk of developing improper water balance. We aim to understand how this genetic change increases the risk of water imbalance through a series of investigations in the test-tube, through a range of studies in animal models, and through analyses of human data and genomic DNA.
描述(由申请人提供):
水平衡失调(即,高钠血症和低钠血症)是最常见的电解质问题;它们在老年人、急性和慢性病患者以及服用某些利尿剂和抗利尿剂药物的患者中非常常见。所有这些诱发因素都存在于退伍军人事务部服务的高比例患者中。异常的水平衡使许多慢性疾病进一步复杂化,并导致预后不良,与潜在疾病的严重程度无关。最近来自严格控制的研究的数据表明,即使是系统水平衡的细微异常也会严重影响协调和认知,并倾向于福尔斯。身体水分平衡的调节是一个复杂的过程,由下丘脑协调,并由肾脏集合管执行;然而,全身张力的中枢传感器仍然不清楚。最近,基于大量的体外数据和动物研究,提出了阳离子通道的瞬时受体电位家族的成员担任这一角色。我们推断,这些基因中的一个共同的单核苷酸多态性可能解释了健康老年人受试者中全身水平衡的个体差异。我们在一个关键的水分调节基因中发现了这样一种多态性,该基因赋予氨基酸变化并导致体外功能异常的蛋白质。重要的是,我们发现,这种多态性的存在与两个健康人群的低钠血症密切相关。此外,效应量很大:该等位基因的单个拷贝的存在使低钠血症的风险增加一倍以上。为了巩固这种关系,我们提出了三个实验目标。在目的I中,我们将对嵌入该多态性的单倍型块进行测序,以确定与我们已知的变体紧密连锁不平衡的其他多态性不能解释该等位基因的作用。尽管我们强烈怀疑是这种情况,但基于我们对该区块中所有编码外显子和剪接点的测序,一个可靠的结论需要对整个单倍型区块进行定相。这也将有助于我们对多民族的调查。在目标II中,我们将测试额外的大人群中这种多态性的存在,以确认其与血清钠浓度和低钠血症的相关性。在目标III中,我们将测试环氧二十碳三烯酸信号传导在正常小鼠的全身水平衡中的作用。其次,我们将在小鼠模型中“敲入”水分调节基因的变异等位基因,以测试它是否能独立地重现人类低钠血症表型。我们进一步建议应用一些生理演习,揭露一个潜在的保水表型。在人类和小鼠基因之间存在极高的保守性,包括受这种多态性影响的氨基酸及其直接背景。值得注意的是,我们将不会创建携带具有该多态性的“额外”等位基因的转基因;我们将用该变体等位基因的鼠类似物替换一个或两个野生型等位基因。此外,在这个目标中,我们将测试环氧二十碳三烯酸系统在野生型和基因敲入小鼠中调节全身水平衡的作用。目前还没有数据说明该系统在体内水平衡中的作用,尽管它通过中枢神经系统传感通道介导张力传感,并且我们现在在我们的初步数据中表明,这种作用被我们的关键多态性打断。
公共卫生关系:
水平衡紊乱是最常见和病态的血液化学问题;它们在老年人、急性和慢性病患者以及服用某些利尿剂和抗利尿剂药物的患者中非常常见。所有这些诱发因素都存在于退伍军人事务部服务的高比例患者中。我们发现,一个关键的水调节蛋白的常见遗传变化增加了发展不适当的水平衡的风险。我们的目标是通过一系列试管研究,通过一系列动物模型研究,以及通过对人类数据和基因组DNA的分析,了解这种遗传变化如何增加水分失衡的风险。
项目成果
期刊论文数量(0)
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DAVID M COHEN其他文献
DAVID M COHEN的其他文献
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{{ truncateString('DAVID M COHEN', 18)}}的其他基金
A Novel Locus in the Regulation of Human Water Balance
人体水平衡调节的新途径
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A Novel Locus in the Regulation of Human Water Balance
人体水平衡调节的新途径
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