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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。