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
• 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
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-15 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7629010
• 关键词: Blood; Blood capillaries; Bone Marrow Transplantation; Calcium-Activated Potassium Channel; Cations; Cell Volumes; Cell membrane; Cervix Neoplasms; Clinical; Clinical Trials; Cooley' s anemia; Dehydration; Development; Doctor of Philosophy; Dominant-Negative Mutation; Epithelial; Erythrocytes; Erythroid; Event; Finding of Mean Corpuscular Hemoglobin; Genes; Genetic; 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; 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; Sum; Supplementation; Syndrome; System; Testing; Thalassemia; Thalassemia intermedia; Time; Translational Research; Up-Regulation; Variant; Vascular Diseases; Work; base; beta Thalassemia; capillary; design; disorder prevention; drug development; gene replacement; hydroxyurea; in vivo; inhibitor/antagonist; mouse model; novel; palliative; polymerization; polypeptide; prevent; programs; prototype; research clinical testing; research study; routine therapy; sickling; standard care; therapeutic target

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 聚合的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红细胞血红蛋白浓度，继发于红细胞体积的调节。已作为镰状细胞病治疗靶标进行研究的这些活性包括 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-电导和至少一种类型的 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。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。

项目成果

Genetic disruption of KCC cotransporters in a mouse model of thalassemia intermedia.

中间型地中海贫血小鼠模型中 KCC 协同转运蛋白的基因破坏。

• DOI: 10.1016/j.bcmd.2019.102389
• 发表时间: 2020
• 期刊: Blood cells, molecules & diseases
• 作者: Shmukler,BorisE;Rivera,Alicia;Bhargava,Parul;Nishimura,Katherine;Kim,EdwardH;Hsu,Ann;Wohlgemuth,JayG;Morton,James;Snyder,LMichael;DeFranceschi,Lucia;Rust,MarcoB;Hubner,ChristianA;Brugnara,Carlo;Alper,SethL
• 通讯作者: Alper,SethL

N-ethylmaleimide activates a Cl(-)-independent component of K(+) flux in mouse erythrocytes.

N-乙基马来酰亚胺可激活小鼠红细胞中 K() 通量的独立于 Cl(-) 的成分。

• DOI: 10.1016/j.bcmd.2013.02.004
• 发表时间: 2013
• 期刊: Blood cells, molecules & diseases
• 作者: Shmukler,BorisE;Hsu,Ann;Alves,Jessica;Trudel,Marie;Rust,MarcoB;Hubner,ChristianA;Rivera,Alicia;Alper,SethL
• 通讯作者: Alper,SethL

Combined genetic disruption of K-Cl cotransporters and Gardos channel KCNN4 rescues erythrocyte dehydration in the SAD mouse model of sickle cell disease.

K-Cl 协同转运蛋白和 Gardos 通道 KCNN4 的联合基因破坏可挽救镰状细胞病 SAD 小鼠模型中的红细胞脱水。

• DOI: 10.1016/j.bcmd.2019.102346
• 发表时间: 2019
• 期刊: Blood cells, molecules & diseases
• 作者: Shmukler,BorisE;Rivera,Alicia;Bhargava,Parul;Nishimura,Katherine;Hsu,Ann;Kim,EdwardH;Trudel,Marie;Rust,MarcoB;Hubner,ChristianA;Brugnara,Carlo;Alper,SethL
• 通讯作者: Alper,SethL

Erythroid-specific inactivation of Slc12a6/Kcc3 by EpoR promoter-driven Cre expression reduces K-Cl cotransport activity in mouse erythrocytes.

• DOI: 10.14814/phy2.15186
• 发表时间: 2022-03
• 期刊: Physiological reports
• 影响因子: 2.5
• 作者: Shmukler BE;Rivera A;Nishimura K;Hsu A;Wohlgemuth JG;Dlott JS;Michael Snyder L;Brugnara C;Alper SL
• 通讯作者: Alper SL