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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：
7245127
负责人：
SETH Leo ALPER
金额：
$ 39.02万
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/7245127
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

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(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。镰刀状红细胞的平均红细胞血红蛋白浓度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，几种红系离子转运体和通道被认为是继红细胞体积调节之后调节红细胞血红蛋白浓度的通道。在这些已被研究为镰状细胞病治疗靶点的活性中，有KCNN/IK1/SK4钙激活的中间电导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-电导，以及至少一种类型的钙离子通透性阳离子电导。K-CI共转运蛋白也被测试为地中海贫血的治疗靶点。编码这些离子转运多肽的基因是血红蛋白疾病的强有力的候选风险修饰基因。这一应用提出了一个普遍假设，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。这一普遍假说将通过旨在追求以下特定目标的实验来验证：目的1.我们将在镰状细胞病小鼠模型中检验红系IK1/Gardos通道基因缺陷将减少病理性红细胞脱水并改善临床严重程度的假说。目的2.我们将在镰状细胞病和中间型β-地中海贫血小鼠模型中验证红系KCC K-CI联合转运体基因缺陷将减少病理性红细胞脱水并改善临床严重程度的假说。目的3.我们将验证以下假设：在镰状细胞病小鼠模型中，红系IK1/Gardos通道和红系KCC K-CI共转运体的联合遗传缺陷将进一步改善临床严重程度。拟议中的实验将通过为近期临床测试正在开发的新药疗法的基因测试提供小鼠模型，从而增加对镰状细胞疾病和地中海贫血的了解。