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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：
SETH Leo ALPER
金额：
$ 2.93万
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/7459154
关键词：
Blood Blood capillaries Bone Marrow Transplantation Calcium-Activated Potassium Channel Cations Cell membrane Cervix Neoplasms Clinical Clinical Trials Cooley&apos s anemia Dehydration Development Doctor of Philosophy Dominant-Negative Mutation Epithelial Erythrocytes Erythroid Event Finding of Mean Corpuscular Hemoglobin Genes Genetic Genetic Models Genetic screening method Growth Hemoglobin Hemoglobinopathies Human In Vitro Ion Transport Ions Lead Mammary gland Mediating Mediator of activation protein Membrane Modeling Molecular Weight Mus Neoplasm Transplantation Nude Mice Numbers Orphan Drugs Ovary Pathologic Pathway interactions Patients Permeability Pharmaceutical Preparations Pharmacotherapy Phase Phenotype Physiological Potassium Channel Publishing Recombinants Regulation Research Personnel Risk Secondary to Severities Severity of illness Sickle Cell Sickle Cell Anemia Sickle Hemoglobin Standards of Weights and Measures Sum Supplementation Syndrome System Testing Thalassemia Thalassemia intermedia Time Translational Research Up-Regulation Variant Work base beta Thalassemia capillary day design disorder prevention drug development gene replacement hydroxyurea in vivo inhibitor/antagonist mouse model novel polymerization polypeptide prevent programs prototype research clinical testing research study sickling therapeutic 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红细胞脱水。平均镰状红细胞的红细胞血红蛋白浓度关键地决定了脱氧诱导血红蛋白聚合的快速相。几种红系离子转运蛋白基于药理学和生理学研究，认为通道调节红细胞血红蛋白浓度继发于红细胞体积的调节。在已经研究的这些活动中，作为镰状细胞病的治疗靶点的是KCNN/IK 1/SK 4 Ca 2+激活的K-通道，电导（Gardos通道），几种类型的KCC K-CI转运蛋白，至少两种类型的红细胞CI” 电导和至少一种类型的Ca 2+可渗透阳离子电导。K-CI共转运蛋白也被测试为地中海贫血的治疗靶点。编码这些离子转运的基因多肽是血红蛋白病的强候选风险调节基因。本申请提出了一般假设，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中的疾病严重程度。这一一般假设将得到检验通过旨在实现以下具体目标的实验：目标1.我们将检验红细胞IK 1/Gardos通道的遗传缺陷将导致减少病理性红细胞脱水，并将改善小鼠模型的临床严重程度，镰状细胞病。目标2.我们将检验红细胞系KCCK-CI共转运蛋白的遗传缺陷将减少病理性红细胞脱水，并将改善小鼠模型的临床严重程度，镰状细胞病和中间型β地中海贫血。目标3.我们将检验红系IK 1/Gardos通道联合遗传缺陷的假设，和红系KCCK-CI共转运蛋白的表达将进一步改善小鼠模型中的临床严重性。镰状细胞病。拟议中的实验将通过提供正在开发的用于近期临床试验的新药物疗法基因测试的小鼠模型。