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：
7030496
负责人：
SETH Leo ALPER
金额：
$ 41.94万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
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：
https://reporter.nih.gov/project-details/7030496
关键词：
Xenopus oocyte cell morphology cellular pathology chloride channels erythrocytes genetic susceptibility hemoglobin Ss ion transport laboratory mouse membrane permeability membrane transport proteins potassium channel potassium ion sickle cell anemia sickling inhibitor thalassemia

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的特征是病理性红细胞脱水。镰状红细胞的平均红细胞血红蛋白浓度关键决定了脱氧诱导的血红蛋白 S 聚合快速阶段之前的滞后时间。根据药理学和生理学研究，认为几种红细胞离子转运蛋白和通道可调节继发于血红蛋白 S 的红细胞血红蛋白浓度。红细胞体积的调节。已作为镰状细胞病治疗靶标进行研究的这些活动包括 KCNN/IK1/SK4 Ca2+ 激活的中等电导 K+ 通道（Gardos 通道）、几种类型的 KCC K-CI 协同转运蛋白、至少两种类型的红细胞 CI- 电导，以及至少一种类型的Ca2+可渗透阳离子电导。 K-CI 协同转运蛋白也已作为地中海贫血的治疗靶点进行了测试。编码这些离子转运多肽的基因是血红蛋白病的强有力的候选风险调节基因。该申请提出了一般假设，即这些转运蛋白和通道活性的基因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实现以下具体目标的实验进行检验：目标 1。我们将检验以下假设：红细胞 IK1/Gardos 通道的遗传缺陷将减少病理性红细胞脱水，并改善镰状细胞病小鼠模型的临床严重程度细胞疾病。目标 2. 我们将测试以下假设：红系 KCC K-CI 协同转运蛋白的遗传缺陷将减少病理性红细胞脱水，并改善镰状细胞病和中间型 β-地中海贫血小鼠模型的临床严重程度。目标 3. 我们将检验以下假设：红系 IK1/Gardos 通道和红系 KCC K-CI 协同转运蛋白的组合遗传缺陷将进一步改善镰状细胞病小鼠模型的临床严重程度。拟议的实验将通过为近期临床测试正在开发的新药物疗法的基因测试提供小鼠模型来增进对镰状细胞病和地中海贫血的了解。