RBC Ion Transporters as Hemoglobinopathy Risk Modifiers
红细胞离子转运蛋白作为血红蛋白病风险调节剂
基本信息
- 批准号:7459154
- 负责人:
- 金额:$ 2.93万
- 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:2006-06-15 至 2010-05-31
- 项目状态:已结题
- 来源:
- 关键词:BloodBlood capillariesBone Marrow TransplantationCalcium-Activated Potassium ChannelCationsCell membraneCervix NeoplasmsClinicalClinical TrialsCooley&aposs anemiaDehydrationDevelopmentDoctor of PhilosophyDominant-Negative MutationEpithelialErythrocytesErythroidEventFinding of Mean Corpuscular HemoglobinGenesGeneticGenetic ModelsGenetic screening methodGrowthHemoglobinHemoglobinopathiesHumanIn VitroIon TransportIonsLeadMammary glandMediatingMediator of activation proteinMembraneModelingMolecular WeightMusNeoplasm TransplantationNude MiceNumbersOrphan DrugsOvaryPathologicPathway interactionsPatientsPermeabilityPharmaceutical PreparationsPharmacotherapyPhasePhenotypePhysiologicalPotassium ChannelPublishingRecombinantsRegulationResearch PersonnelRiskSecondary toSeveritiesSeverity of illnessSickle CellSickle Cell AnemiaSickle HemoglobinStandards of Weights and MeasuresSumSupplementationSyndromeSystemTestingThalassemiaThalassemia intermediaTimeTranslational ResearchUp-RegulationVariantWorkbasebeta Thalassemiacapillarydaydesigndisorder preventiondrug developmentgene replacementhydroxyureain vivoinhibitor/antagonistmouse modelnovelpolymerizationpolypeptidepreventprogramsprototyperesearch clinical testingresearch studysicklingtherapeutic target
项目摘要
Sickle cell disease and thalassemia are characterized by pathological red cell dehydration. The mean
corpuscular hemoglobin concentration of sickle erythrocytes critically determines the lag time preceding the
rapid phase of deoxygenation-induced polymerization of hemoglobinS. Several erythroid ion transporters
and channels are believed on the basis of pharmacological and physiological studies to regulate red cell
hemoglobin concentration secondary to regulation of red cell volume. Among these activities already studied
as therapeutic targets in sickle cell disease are the KCNN/IK1/SK4 Ca2+-activated K" channel of intermediate
conductance (Gardos channel), several types of KCC K-CIcotransporters, at least two types of erythroidCI"
conductance, and at least one type of Ca2+-permeable cation conductance. The K-CI cotransporters have
also been tested as therapeutic targets for thalassemia. The genes encoding these ion-transporting
polypeptides are strong candidate risk modifier genes for the hemoglobinopathies. This application
proposes the general hypothesis that genetic modulation of these transporter and channel activities will
modulate disease severity in mouse models of hemoglobinopathies. This general hypothesis will be tested
by experiments designed to pursue the following Specific Aims:
Aim 1. Wewill test the hypothesis that genetic deficiency of the erythroid IK1/Gardos channel will
decrease pathologic red cell dehydration and will ameliorate clinical severity in mouse models of
sickle cell disease.
Aim 2. Wewill test the hypothesis that genetic deficiency of erythroid KCCK-CI cotransporters will
decrease pathologic red cell dehydration and will ameliorate clinical severity in mouse models of
sickle cell disease and of p-thalassemia intermedia.
Aim 3. Wewill test the hypothesis that combined genetic deficiency of erythroid IK1/Gardos channel
and of erythroid KCCK-CI cotransporters will further ameliorate clinical severity in mouse models of
sickle cell disease.
The proposed experiments will increase understanding of sickle cell disease and thalassemia by providing
mouse models for genetic tests of new drug therapies under development for near-term clinical testing.
镰状细胞病和地中海贫血的特征是病理性的红细胞脱水。中庸之道
镰刀状红细胞的红细胞血红蛋白浓度关键决定了发病前的滞后时间。
脱氧诱导的血红蛋白聚合的快速阶段。几种红系离子转运蛋白
在药理学和生理学研究的基础上,人们认为经络可以调节红细胞
其次是调节红细胞体积的血红蛋白浓度。在已研究的这些活动中
镰状细胞病的治疗靶点是中间体的KCNN/IK1/SK4钙激活K“通道
电导(Gardos通道),几种类型的KCC K-CI转运体,至少两种类型的红细胞性CI“
电导性,以及至少一种类型的钙离子渗透性阳离子电导性。K-CI联合运输机已经
也被测试为地中海贫血的治疗靶点。编码这些离子运输的基因
多肽是血红蛋白疾病的强有力的候选风险修饰基因。此应用程序
提出了一个普遍的假设,即这些转运蛋白和通道活动的遗传调节将
调节血红蛋白病小鼠模型的疾病严重程度。这一普遍假设将得到检验。
通过旨在实现以下具体目标的实验:
目的1.我们将检验以下假设:红系IK1/Gardos通道的遗传缺陷将
减少病理性红细胞脱水,并将改善临床严重程度的小鼠模型
镰状细胞病。
目的2.我们将检验以下假设:红系KCCK-CI共转运体的遗传缺陷将
减少病理性红细胞脱水,并将改善临床严重程度的小鼠模型
镰状细胞病和中间型地中海贫血。
目的3.我们将检验红系IK1/Gardos通道联合遗传缺陷的假说
而红系KCCK-CI共转运蛋白的表达将进一步改善小鼠模型的临床严重程度
镰状细胞病。
拟议的实验将增加对镰状细胞疾病和地中海贫血的了解
用于新药疗法基因测试的小鼠模型正在开发中,用于近期临床测试。
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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SETH Leo ALPER其他文献
SETH Leo ALPER的其他文献
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{{ truncateString('SETH Leo ALPER', 18)}}的其他基金
Molecular Mechanism of APOL1 Associated Kidney Disease
APOL1相关肾脏疾病的分子机制
- 批准号:
8486603 - 财政年份:2013
- 资助金额:
$ 2.93万 - 项目类别:
Molecular Mechanism of APOL1 Associated Kidney Disease
APOL1相关肾脏疾病的分子机制
- 批准号:
8791547 - 财政年份:2013
- 资助金额:
$ 2.93万 - 项目类别:
Molecular Mechanism of APOL1 Associated Kidney Disease
APOL1相关肾脏疾病的分子机制
- 批准号:
9011946 - 财政年份:2013
- 资助金额:
$ 2.93万 - 项目类别:
Molecular Mechanism of APOL1 Associated Kidney Disease
APOL1相关肾脏疾病的分子机制
- 批准号:
9212011 - 财政年份:2013
- 资助金额:
$ 2.93万 - 项目类别:
Molecular Mechanism of APOL1 Associated Kidney Disease
APOL1相关肾脏疾病的分子机制
- 批准号:
8695481 - 财政年份:2013
- 资助金额:
$ 2.93万 - 项目类别:
RBC Ion Transporters as Hemoglobinopathy Risk Modifiers
红细胞离子转运蛋白作为血红蛋白病风险调节剂
- 批准号:
7030496 - 财政年份:2006
- 资助金额:
$ 2.93万 - 项目类别:
RBC Ion Transporters as Hemoglobinopathy Risk Modifiers
红细胞离子转运蛋白作为血红蛋白病风险调节剂
- 批准号:
7629010 - 财政年份:2006
- 资助金额:
$ 2.93万 - 项目类别:
RBC Ion Transporters as Hemoglobinopathy Risk Modifiers
红细胞离子转运蛋白作为血红蛋白病风险调节剂
- 批准号:
7435221 - 财政年份:2006
- 资助金额:
$ 2.93万 - 项目类别:
RBC Ion Transporters as Hemoglobinopathy Risk Modifiers
红细胞离子转运蛋白作为血红蛋白病风险调节剂
- 批准号:
7245127 - 财政年份:2006
- 资助金额:
$ 2.93万 - 项目类别:
RBC Ion Transporters as Hemoglobinopathy Risk Modifiers
红细胞离子转运蛋白作为血红蛋白病风险调节剂
- 批准号:
7665605 - 财政年份:2006
- 资助金额:
$ 2.93万 - 项目类别:
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