Genetic Determinants of Erythrocyte Hydration
红细胞水合的遗传决定因素
基本信息
- 批准号:7391161
- 负责人:
- 金额:$ 57.76万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2006
- 资助国家:美国
- 起止时间:2006-04-01 至 2010-03-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAffectAnemiaAreaBioinformaticsCandidate Disease GeneCell VolumesCell membraneCellsChronicClassificationClinicalCytoskeletal ProteinsDataDatabasesDehydrationDevelopmentEnvironmentErythrocytesExposure toFunctional disorderFutureGenesGeneticGenetic DeterminismGenomeGenomicsHematological DiseaseHemoglobinHemoglobin SC DiseaseHereditary DiseaseHereditary SpherocytosisHeritabilityHumanHydration statusInbred StrainInbred Strains MiceIndividualInheritedIon TransportIonsIronKiller CellsKnock-in MouseLeadLocalizedMeasurementMediatingMegaloblastic AnemiaMembraneMembrane Transport ProteinsMethodsModificationMouse StrainsMusOrganPathway interactionsPatientsPhasePhenotypePlayPotassium ChannelPredispositionPropertyPumpQuantitative Trait LociRegulationRegulator GenesRegulatory PathwayRoleSeverity of illnessSickle CellSickle Cell AnemiaSurfaceSyndromeTestingTherapeutic AgentsVariantbaseexperiencein vivoinhibitor/antagonistmouse modelnovelnovel therapeuticsperipheral bloodpreventresearch studysicklingstomatocytic anemiatherapeutic targettrait
项目摘要
Changes in the function of transporters embedded into the cell membrane have been associated with
erythrocyte dehydration in sickle cell anemia, Hb CC and SC diseases, hereditary spherocytosis and
xerocytosis. Dehydrated cells are the most likely to sickle and produce vaso-occlusion; thus, specific
therapies are being developed to diminish dehydration in vivo. The physiologically important
regulators/determinants of activity of these pathways are not known, thus impeding the identification of
subsets of patients more likely to experience cell dehydration and vaso-occlusion.
We propose to identify physiologically important genes affecting the function of ion transport pathways and
cell hydration in mouse and eventually human erythrocytes. We will use inbred mouse strains to identify
quantitative tract loci (QTLs) and ultimately individual genes that modulate red cell hydration and transport.
We have already identified inbred mouse strains with large differences in cell hydration: from the appropriate
crosses, QTL analysis will be performed to focus on areas of the genome associated with the different
phenotype, and identify the gene(s) involved.
We also propose a detailed phenotypic characterization of the erythrocyte ion content and transport
properties, focused on three pathways known to mediate dehydration (Gardos channel, K-CIcotransport,
and Na-K pump), in 11 normal inbred mouse strains. These strains are widely used, with abundantly
available genetic and phenotypic information. We will set-up informative crosses to identify specific QTLs
associated with meaningful differences in transport activities.
Definition of the genes influencing erythrocyte hydration and ion transport in the mouse will enlighten
explorations in the sickle mouse model, and will allow testing of candidate genes using knock in/out
experiments. The ultimate intent is to validate in future studies the mouse candidate genes with appropriate
association studies in patients. We anticipate that these studies will lead to identification of novel genes
relevant to pathophysiology of sickle cell syndromes and other anemias, and of potential new therapeutic
targets, markers of disease severity, and indicators of susceptibility to specific therapies.
嵌入细胞膜的转运蛋白功能的变化与
镰状细胞性贫血、Hb CC和SC疾病、遗传性球形红细胞增多症和
干细胞症。脱水细胞最有可能镰刀状并产生血管闭塞;因此,特异性
正在开发减少体内脱水的疗法。生理上重要的
这些途径的活性的调节因子/决定因子是未知的,因此阻碍了对
患者亚群更可能经历细胞脱水和血管闭塞。
我们建议确定影响离子转运途径功能的生理学重要基因,
小鼠和最终人类红细胞中的细胞水合作用。我们将使用近交系小鼠来鉴定
数量束基因座(QTL)和最终的个体基因,调节红细胞水合和运输。
我们已经确定了在细胞水合作用方面存在很大差异的近交系小鼠品系:
杂交,QTL分析将集中在与不同的基因组相关的基因组区域,
表型,并鉴定相关基因。
我们还提出了一个详细的表型表征红细胞离子含量和运输
性质,集中在已知介导脱水的三种途径(Gardos通道,K-CI转运,
和Na-K泵)。这些菌株被广泛使用,
遗传和表型信息。我们将建立信息性杂交来识别特定的QTL
与运输活动中有意义的差异相关。
定义影响小鼠红细胞水合和离子转运的基因将启发
在镰状小鼠模型的探索,并将允许使用敲入/敲出测试候选基因
实验最终目的是在未来的研究中验证小鼠候选基因,
患者的相关研究。我们预期这些研究将导致新基因的鉴定
与镰状细胞综合征和其他贫血的病理生理学以及潜在的新治疗方法相关
靶点、疾病严重程度的标志物和对特定疗法敏感性的指标。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Carlo Brugnara其他文献
Carlo Brugnara的其他文献
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{{ truncateString('Carlo Brugnara', 18)}}的其他基金
EFFECT OF DIETARY MAGNESIUM ON RED CELL MAGNESIUM, VOLUME AND K/CL COTRANSPORT
膳食镁对红细胞镁、容量和 K/CL 协同转运的影响
- 批准号:
7204657 - 财政年份:2005
- 资助金额:
$ 57.76万 - 项目类别:
EFFECT OF DIETARY MAGNESIUM ON RED CELL MAGNESIUM, VOLUME AND K/CL COTRANSPORT
膳食镁对红细胞镁、容量和 K/CL 协同转运的影响
- 批准号:
6120793 - 财政年份:1998
- 资助金额:
$ 57.76万 - 项目类别:
LONG TERM USE OF CLOTRIMAZOLE AS A THERAPEUTIC AGENT FOR SICKLE CELL DISEASE
长期使用克霉唑作为镰状细胞病的治疗剂
- 批准号:
6120784 - 财政年份:1998
- 资助金额:
$ 57.76万 - 项目类别:
LONG TERM USE OF CLOTRIMAZOLE AS A THERAPEUTIC AGENT FOR SICKLE CELL DISEASE
长期使用克霉唑作为镰状细胞病的治疗剂
- 批准号:
6220564 - 财政年份:1998
- 资助金额:
$ 57.76万 - 项目类别:
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