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:
    7245127
  • 负责人:
  • 金额:
    $ 39.02万
  • 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

项目摘要

Description (provided by applicant): 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 hemoglobin S. 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-CI cotransporters, at least two types of erythroid CI- 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. We will 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. We will test the hypothesis that genetic deficiency of erythroid KCC K-CI cotransporters will decrease pathologic red cell dehydration and will ameliorate clinical severity in mouse models of sickle cell disease and of beta-thalassemia intermedia. Aim 3. We will test the hypothesis that combined genetic deficiency of erythroid IK1/Gardos channel and of erythroid KCC K-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.
描述(由申请人提供):镰状细胞病和地中海贫血以病理性红细胞脱水为特征。镰状红细胞红细胞血红蛋白的平均浓度至关重要地决定了脱氧诱导的血红蛋白s聚合快速期之前的滞后时间。根据药理学和生理学研究,几种红离子转运体和通道对红细胞血红蛋白浓度的调节仅次于对红细胞体积的调节。在这些已经被研究为镰状细胞病治疗靶点的活性中,有KCNN/IK1/SK4 Ca2+激活的中间传导K+通道(Gardos通道),几种类型的KCC K-CI共转运体,至少两种类型的红系CI-传导,以及至少一种类型的Ca2+可渗透阳离子传导。K-CI共转运体也被测试为地中海贫血的治疗靶点。编码这些离子转运多肽的基因是血红蛋白病强有力的候选风险修饰基因。这一应用提出了一个普遍的假设,即这些转运体和通道活动的遗传调节将调节血红蛋白病小鼠模型中的疾病严重程度。这一一般假设将通过旨在追求以下具体目标的实验来检验:目的1。我们将在小鼠镰状细胞病模型中检验红细胞IK1/Gardos通道的遗传缺陷会减少病理性红细胞脱水并改善临床严重程度的假设。目标2。我们将在镰状细胞病和-地中海贫血的小鼠模型中检验红细胞KCC - K-CI共转运体的遗传缺陷会减少病理性红细胞脱水,并改善临床严重程度的假设。目标3。我们将验证红细胞IK1/Gardos通道和红细胞KCC K-CI共转运体的联合遗传缺陷将进一步改善小鼠镰状细胞病模型的临床严重程度的假设。拟议的实验将通过为正在开发的用于近期临床试验的新药物疗法的基因测试提供小鼠模型,增加对镰状细胞病和地中海贫血的了解。

项目成果

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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:
    $ 39.02万
  • 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:
    $ 39.02万
  • 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:
    $ 39.02万
  • 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:
    $ 39.02万
  • 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:
    $ 39.02万
  • 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:
    $ 39.02万
  • 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:
    $ 39.02万
  • 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:
    7459154
  • 财政年份:
    2006
  • 资助金额:
    $ 39.02万
  • 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:
    $ 39.02万
  • 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:
    $ 39.02万
  • 项目类别:

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Fine Structure of Blood Capillaries and Striated Muscle in Fish
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  • 批准号:
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  • 财政年份:
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